The mammalian START domain protein family in lipid transport in health and disease

in Journal of Endocrinology
Author: Barbara J Clark
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  • Department of Biochemistry and Molecular Biology, and the Center for Genetics and Molecular Medicine, School of Medicine, University of Louisville, Louisville, Kentucky 40292, USA

Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

Abstract

Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

Introduction

Lipid transport proteins play an important role in non-vesicular trafficking of cholesterol, phospholipids, and sphingolipids between biological membranes to help maintain the proper cholesterol:phospholipid:sphingolipid distribution (reviewed in Prinz (2007) and Lev (2010)). Cholesterol content is maintained at relatively low levels within the endoplasmic reticulum (ER) and mitochondrial membranes compared with the plasma membrane (PM; Mesmin & Maxfield 2009). The source of PM cholesterol is from both de novo synthesis in the ER and cellular uptake of low-density lipoprotein (LDL)-derived cholesterol. De novo-synthesized cholesterol is rapidly transferred to the PM by non-vesicular trafficking mechanism(s), implicating a role for soluble sterol transport proteins (Maxfield & van Meer 2010). Receptor-mediated endocytosis of LDL delivers lipoproteins to the late endosomes/lysosomes where free cholesterol is hydrolyzed from cholesterol esters (Goldstein & Brown 2009). The free cholesterol is recycled back to the PM or transported to the ER. In the PM, cholesterol can be found clustered with sphingolipids into detergent-resistant protein–lipid microdomains referred to as lipid rafts (Danielsen & Hansen 2003, Rajendran & Simons 2005, Hanzal-Bayer & Hancock 2007). Functionally, lipid rafts are proposed to provide an organized membrane region for signaling and other functions (Lingwood & Simons 2010). Changes in ER membrane cholesterol levels signal for changes in gene expression leading to altered cholesterol metabolism while transport of cholesterol to mitochondria is required for production of steroid hormones and bile acids. Thus, it has long been appreciated that maintaining proper cholesterol distribution within the cell is important for cholesterol homeostasis and membrane function (Qin et al. 2006, Maxfield & van Meer 2010). There are two major gene families for lipid transfer proteins with specificity for sterols: the steroidogenic acute regulatory protein (StAR)-related lipid-transfer (START) domain family and the oxysterol-binding protein (OSBP) family, which includes the OSBP-related proteins (ORPs). This review focuses on the role of the mammalian START domain family in lipid trafficking and the implications for dysregulation of START protein expression in disease states. The OSBP/ORP family has been reviewed by others (Prinz 2007, Ngo et al. 2010).

The START domain protein family

The START domain is defined by a conserved sequence of ∼210 amino acids that folds into an α/β helix-grip structure forming a hydrophobic pocket for binding sterols and other lipids (Ponting & Aravind 1999, Iyer et al. 2001). The helix-grip fold is used to define a large superfamily of proteins that bind hydrophobic lipids, classified as the SRPBCC protein superfamily on NCBI's Conserved Domain Database (START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC, cl14643 NCBI; Marchler-Bauer et al. 2009). BLASTP searches have identified START domains in genomes from plants, bacteria, protists, and animals, but not in archaea or yeast (Schrick et al. 2004). START domains are relatively rare in bacteria and protist genomes, and to date, there is no evidence that these proteins are expressed. Proteins containing the START domain are most abundant in plants and are highly represented in proteins that contain a homeodomain, suggesting a role in transcription (Schrick et al. 2004). The homeodomain–START domain structure has only been found in plant proteins. Coupling the START domain with other motifs is, however, a common theme as START domains in other phyla are found in multi-domain proteins that provide additional functions such as protein localization, enzymatic activity, or signaling (Ponting & Aravind 1999, Iyer et al. 2001).

The mammalian START domain protein family is well characterized and is composed of 15 members that group into six subfamilies based on the sequence and ligand similarities (Ponting & Aravind 1999, Soccio et al. 2002; Table 1). In very general terms, the subfamilies can be classified into cholesterol- and oxysterol binding proteins (STARD1/D3 and STARD4/D5/D6 subfamilies), the phospholipid- and sphingolipid-binding proteins (STARD2 (phosphatidylcholine transfer protein, PCTP)/D7/D10/D11 subfamily), the multi-domain proteins containing either putative Rho-GTPase signaling function (STARD8/12/13 subfamily) or thioesterase activity (STARD14/15 subfamily), and the STARD9 subfamily composed of a single member of unknown function that is not further discussed (Soccio et al. 2002, Soccio & Breslow 2003, Alpy & Tomasetto 2005). The crystal structures for the START domains of hSTARD3/metastatic axillary lymph node 64 kDa protein (MLN64) and mSTARD4 were the first to be solved and showed an α/β helix-grip fold with a nine-stranded anti-parallel β-sheet forming a U-shaped hydrophobic cleft that binds the ligand and is flanked by amino- and carboxyl-terminal α helices (Tsujishita & Hurley 2000, Romanowski et al. 2002). The carboxyl-terminal α helix is proposed to serve as a ‘cap’ to the ligand-binding site, with lipid access to the binding pocket requiring a conformational change in the START domain and movement of the C-terminal helix (Baker et al. 2005, Bose et al. 2008a,b). To date, crystal structures for the START domains of hSTARD1, hSTARD5, hSTARD2/PCTP, STARD11/CERT, hSTARD13, and hSTARD14 have been reported and the data confirm the basic three-dimensional helix-grip fold structure across the five mammalian subfamilies that defines this family of proteins (Roderick et al. 2002, Kudo et al. 2008, 2010, Thorsell et al. 2011). Modeling of START domain conformational changes and mechanisms for cholesterol absorption/desorption have been reviewed elsewhere (Alpy & Tomasetto 2005, Miller 2007, Lavigne et al. 2010).

Table 1

Characteristics of the mammalian START domain protein family members

START subfamilySTART proteinOther name(s)Domain structureTissue distribution*Cellular locationLipid bindingFunction/metabolic pathway
STARD1/D3STARD1StARAdrenal, ovary, testis, brainMitochondria,a,b,cCholesterold,eSteroidogenesis1
STARD3MLN64MENTAL-STARTPlacenta, breast, macrophages*Transmembrane, late endosomes,a,b,cCholesterold,eendosomal cholesterol efflux2
STARD4STARD4STARTLiver, macrophages, kidneyCytosolica≫ERa,b mitochondriabCholesterol¥,dACAT activation3
STARD5STARTMacrophage kidney proximal tubulesCytosolic≫ER, Golgi, PMaCholesterol, 25HC¥,dER stress response4 ?
STARD6STARTTestis germ cellCytosolicc, mitochondriabCholesterold,e?
STARD2STARD2PC-TPSTARTLiver, lung*ER/Golgi,bPCfGlycolysis5, FA synthesis5
STARD7 STARD7-IGTT-1Liver*Cytosolicc mitochondriacPCe?
STARD10PCTP likeSTARTLiver, kidney, testis, colon*CytosoliccPC>PEe?
STARD11CERT, GPBPΔ26, COL4A3BP Liver*ER/Golgi,bCeramide¥,eER→Golgi ceramide transport6
The RhoGAP multidomain proteinsSTARD8DLC-3Cancer*Focal adhesions?Tumor suppressor7
STARD12DLC-1Cancer*Focal adhesions PMa?Cytoskeletal organization8 tumor suppressor8
STARD13DLC-2Endothelial cells*Focal adhesionsCharged lipidd (?)Tumor suppressor9
STARD9STARD9?Cytosolicc ???
The thioesterase multidomain proteinsSTARD14ACOT11_v2, BFIT2Brown adipose tissueCytosolicc ?Fatty acidd (?)Medium chain fatty-acyl-coA hydrolysis10
STARD15ACOT12LiverCytosolicc?Acetyl-coA hydrolysis11

StAR, steroidogenic acute regulatory protein; START, StAR-related lipid transfer domain; MLN64, metastatic axillary lymph node 64 kDa protein; PC-TP, phosphatidylcholine transfer protein; GTT1, gestational trophoblastic tumor gene-1; CERT, ceramide transfer protein; GPBP, Goodpasture antigen-binding protein; COL4A3BP, collagen-type IV α3 binding protein; DLC, deleted in liver cancer; ACOT, acyl-CoA thioesterase; BFIT2, brown fat-inducible thioesterase-2; ss, signal sequence; MENTAL, MLN64-N terminal domain; PH, pleckstrin homology domain; FFAT, peptide EFFDAxE; SAM, sterile α domain; Hotdog, conserved domain structure for acyl-coenzyme A thioesterase family that has thioesterase activity; ACAT, acyl-CoA:cholesterol acyl transferase activity. Cellular location: domains direct subcellular location; abased on immunohistochemistry data for endogenous protein expression; bbased on in vitro activity; cbased on structure. Lipid binding: ¥direct ligand binding assay; dmodeled based on structure; ebased on in vitro lipid extraction assay; fshown in crystal (Tsujishita & Hurley 2000, Roderick et al. 2002, Olayioye et al. 2005, Rodriguez-Agudo et al. 2005, Murcia et al. 2006, Bose et al. 2008a,b, Kudo et al. 2008, Rodriguez-Agudo et al. 2008, Barbar et al. 2009, Horibata & Sugimoto 2010, Thorsell et al. 2011). Function: 1(Stocco 2001); 2(Alpy & Tomasetto 2006); 3(Rodriguez-Agudo et al. 2011); 4(Soccio et al. 2005, Chen et al. 2009); 5(Scapa et al. 2008); 6(Hanada et al. 2009); 7–9(Durkin et al. 2007a,b); 10,11(Kirkby et al. 2010).

Ubiquitous expression with the major tissues studied listed.

Restricted expression (Adams et al. 2001, Stocco 2001, Soccio et al. 2002, Strauss et al. 2003, Gomes et al. 2005, Rodriguez-Agudo et al. 2005, Durkin et al. 2007a,b, Kanno et al. 2007a,b, Chen et al. 2009, Kirkby et al. 2010, Mencarelli et al. 2010, Rodriguez-Agudo et al. 2011). Note that STARD4 and STARD5 mRNA have been detected at low levels in heart; therefore, they may have a broader expression.

Cholesterol trafficking and homeostasis

Intracellular cholesterol levels are tightly regulated by controlling biosynthetic and degradation pathways. There are several excellent reviews on cholesterol homeostasis and cholesterol trafficking (Russell 2003, Soccio & Breslow 2004, Prinz 2007, Brown & Goldstein 2009, Mesmin & Maxfield 2009, Maxfield & van Meer 2010, Wollam & Antebi 2011), and only a brief overview of these topics is provided to set the cellular context for START protein function(s). The major regulatory step for cholesterol biosynthesis is the expression and activation of the enzyme HMG-CoA reductase (HMGR). HMGR transcription is controlled by sterol regulatory element-binding protein-2 (SREBP2), a member of the basic helix–loop–helix–leucine zipper (bHLH-Zip) transcription factor family that is encoded by the SREBP2 gene (Hua et al. 1993, Yokoyama et al. 1993, Sakai & Rawson 2001). SREBP2, however, is a proteolytic fragment of a larger transmembrane protein of the ER that forms a protein complex composed of SREBP, SREBP-cleavage-activating protein (SCAP), and insulin-induced genes 1 and 2 (INSIGs) that functions as a cellular cholesterol sensor. When ER cholesterol levels decline below some threshold level, SREBP-SCAP dissociates from INSIGs and moves to the Golgi apparatus where two proteolytic cleavages releases a ∼50 kDa N-terminal fragment that translocates to the nucleus and activates target gene transcription (Anderson 2003; Fig. 1). Major target genes induced by SREBP2 in the liver are within the cholesterol biosynthetic pathway including HMGR and the LDL receptor (LDLR) (Horton et al. 2003). A resulting increase in cholesterol synthesis (HMGR) and uptake (LDLR) increases intracellular cholesterol levels. The resulting increase in ER cholesterol stabilizes the INSIG-SCAP-SREBP2 complex within the ER and thereby suppresses SREBP2 processing and subsequent transcriptional function(s). Cholesterol is also converted to cholesterol esters by acyl-CoA:cholesterol acyl transferase activity (ACAT), an enzyme localized to the ER. An increase in ER cholesterol levels activates ACAT leading to increased cholesterol ester synthesis.

Figure 1
Figure 1

Model for non-vesicular cholesterol trafficking by the START domain proteins. The cholesterol-binding START proteins are shown at subcellular locations identified by immunohistochemistry (Alpy et al. 2001, Rodriguez-Agudo et al. 2005, Chen et al. 2009). STARD4 stimulates ACAT activity and increases CE synthesis and, therefore, is depicted in close proximity to ACAT at the ER membrane (Rodriguez-Agudo et al. 2011). STARD5 does not stimulate ACAT activity and is shown at different ER sites than STARD4 to indicate potential different functions. The SREBP2 pathway is cartooned to show activation of SREBP2 target genes HMGR, LDLR, and STARD4. The ER to PM and PM to ER cholesterol trafficking is shown to be mediated by a START protein. Although no data have directly demonstrated START proteins in this directional cholesterol trafficking pathway, STARD5 is presented as shuttling cholesterol from the PM to the ER as an example for a START protein in this process based on the apical membrane association renal proximal tubule cells (Chen et al. 2009). Cholesterol transport to mitochondria by STARD1 and STARD4. STARD1 binds cholesterol and facilitates its translocation into the matrix to the P450scc or CYP27A1 enzyme for steroid hormone or oxysterol synthesis respectively. Cholesterol in late endosome/lysosomes is transported to the PM and ER. STARD3/MLN64 in late endosomes is depicted as the intermediate between late endosome/lysosome cholesterol and a soluble cytoplasmic START protein, potentially STARD4 or STARD5. STARD3/MLN64 may obtain cholesterol from NPC2 or MENTHO directly or from NPC1 (see text for details). Cholesterol accumulation in the ER will promote ER stress that can induce STARD5 and STARD4 expression. The purpose for START protein induction upon ER stress is not known and future studies are required to determine whether they are protective or detrimental to the stress response. Solid arrows, vesicular transport; dashed arrows, non-vesicular transport.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0313

Cholesterol metabolism to bile acids in the liver represents the major route for cholesterol clearance. There are two pathways for bile acid biosynthesis, the classical pathway that is initiated in the cytosol and the alternative pathway in mitochondria (reviewed in Russell 2003). In liver mitochondria, cholesterol is hydroxylated on the side chain at position C27 or C25 by the cytochrome P450 enzyme CYP27A1 to produce the oxysterols 27-hydroxycholesterol (27HC) or 25-hydroxycholesterol (25HC) (Li et al. 2007). In addition to simply serving as intermediates in bile acid biosynthetic pathway, 27HC and 25HC are cellular signals that help control cholesterol homeostasis by repressing cholesterol synthesis and enhancing cholesterol efflux. 27HC and 25HC bind to INSIGs and block SREBP-SCAP translocation to the Golgi, thereby repressing SREBP2-dependent pathways (cholesterol synthesis; Radhakrishnan et al. 2007, Sun et al. 2007). In addition, 27HC and 25HC are ligands for the liver X receptor alpha (LXRα), a nuclear receptor that regulates lipid metabolism to help maintain cholesterol homeostasis. LXRα directly activates transcription of the gene encoding the ATP-binding cassette A1 (ABCA1), a cholesterol transporter located in the PM that is important for cholesterol efflux from extra-hepatic cells. Another LXRα target gene is SREBP1 that encodes SREBP1c, another ER membrane-bound SREBP protein that has an N-terminal bHLH-Zip transcription factor that activates genes that encode enzymes in the fatty acid biosynthesis pathway.

Macrophages also convert cholesterol to 27HC in mitochondria using CYP27A1. In extra-hepatic cells, the C27 hydroxyl group of 27HC can be oxidized to a carboxylic acid generating 3β-hydroxy-5-cholestenoic acid, a soluble bile acid precursor that can be secreted and taken up by the liver where it can be further metabolized to bile acids (Babiker & Diczfalusy 1998, Bjorkhem et al. 1999). Thus, the action of CYP27A1 and production of 27HC in macrophages can decrease cellular cholesterol levels by two mechanisms; activation of the LXR-dependent pathway leading to enhanced cholesterol efflux via ABCA1 and production of soluble 3β-hydroxy-5-cholestenoic acid. These are important adaptive responses since macrophages scavenge oxidized-LDL and accumulate lipids in the process of foam cell development. The mechanisms that modulate oxysterol production can have an impact on overall cholesterol homeostasis in liver and macrophages.

Disorders in cholesterol homeostasis are recognized as important contributors to disease states associated with dyslipidemia, e.g. atherosclerosis, fatty liver disease, diabetes, and cancer. This review highlights the current literature that implicates dysregulation of START protein expression in several of these disease states.

The cholesterol/oxysterol-binding START proteins

STARD1/STARD3 subfamily: the membrane-targeted START proteins

StAR is the founding member of the START domain protein family and is expressed predominantly in the adrenal and gonads where it functions to bind cholesterol and facilitate its transfer from the outer to the inner mitochondrial membrane to initiate steroid hormone biosynthesis (Clark et al. 1994, Stocco & Clark 1996). StAR is unique among START family members in that it contains a mitochondria-targeting sequence, a classical amino-terminal amphipathic helix that directs the protein to the mitochondria. It is a nuclear-encoded phosphoprotein that is synthesized in the cytosol as a 37 kDa precursor protein. Mitochondrial import and processing of the precursor produce a 32 kDa intermediate product and a mature 30 kDa form that is localized within the matrix (reviewed in Stocco (2001)). Phosphorylation of the 37 kDa StAR protein at Ser194/195 (mouse/human) by protein kinase A is required for maximal activity (Arakane et al. 1997, Fleury et al. 2004, Jo et al. 2005, Dyson et al. 2008). Although the detailed mechanism for StAR-mediated cholesterol transfer across the mitochondrial membranes is not established, structural, biophysical, and biochemical studies have provided significant insight into this process. One study has shown that the processing of newly synthesized 37 kDa STAR is important for cholesterol transfer function while other reports support that association of the START domain with the outer mitochondrial membrane is sufficient to promote cholesterol transfer (Arakane et al. 1996, 1998, Artemenko et al. 2001, Bose et al. 2002, Baker et al. 2007). Structural modeling and biophysical studies indicate that conformational changes, e.g. movement of the C-terminal α-helix, a pH-dependent molten globule transition, are important to promote cholesterol release and activate cholesterol transfer across the mitochondrial membranes (Bose et al. 1999, Baker et al. 2005, Yaworsky et al. 2005, Murcia et al. 2006, Barbar et al. 2009, Fluck et al. 2011). Cholesterol desorption into the intramembrane space for uptake by the inner membrane has been suggested for StAR functioning independent of cholesterol transfer (Christenson & Strauss 2001). However, more recent biochemical studies indicate functional interactions between StAR and components of a putative cholesterol transfer channel, suggesting a multi-protein complex transfer mechanism for cholesterol movement from the outer to the inner mitochondrial membrane (Hauet et al. 2005, Bose et al. 2008a,b, Rone et al. 2009). There is evidence to suggest that StAR phosphorylation occurs at the mitochondria and that StAR phosphorylation is important for processing to the 30 kDa protein (Artemenko et al. 2001, Bose et al. 2008a,b, Dyson et al. 2008). Once StAR has been imported into the mitochondrial matrix and processed to the 30 kDa mature form, it is no longer functional since it is no longer accessible to the mitochondrial outer membrane. A more in-depth description of these current models of StAR mechanism of action can be found in recent reviews (Miller 2007, Papadopoulos et al. 2007, Lavigne et al. 2010). Although a consensus for a mechanism for StAR-mediated cholesterol transport requires further study, all models are similar to the requirement for continual synthesis of the 37 kDa StAR in response to tropic hormone stimulation to maintain cholesterol transfer into the mitochondria.

Metastatic axillary lymph node protein 64 (MLN64) was identified by differential screening of a cDNA library for amplified products in breast cancer-derived MLN and was found to contain a domain that shared 33% sequence identity and 53% sequence similarity with the human StAR START domain (Tomasetto et al. 1995, Moog-Lutz et al. 1997). Thus, MLN64 was recognized as a START protein and named STARD3. STARD3/MLN64 is a transmembrane protein that is targeted to the late endosomes by an N-terminal MENTAL (MLN64-N-terminal) domain with a predicted membrane topology of four transmembrane helices that orients the C-terminal START domain facing the cytoplasm (Tomasetto et al. 1995, Alpy et al. 2001).

Overall, the two members of the STARD1/D3 subfamily are similar in that the START domain for both proteins binds only cholesterol and additional sequences or domains localize the proteins to specific subcellular compartments. The differential subcellular localization of these START proteins suggests different functions in cholesterol trafficking (Table 1).

STARD1 and cholesterol transport to mitochondria

Acute regulation of steroidogenesis

Steroidogenic cells of the adrenal and gonads respond to tropic hormone stimulation by rapidly increasing the rate of steroid hormone biosynthesis. The first enzymatic reaction of steroidogenesis is the conversion of cholesterol to pregnenolone by the cholesterol side-chain cleavage complex, which is localized to the mitochondrial inner membrane. This step requires the delivery of the substrate cholesterol from cellular stores to the inner mitochondrial membrane, a process that occurs rapidly in response to tropic hormone stimulation and requires de novo protein synthesis. Thus, a protein that is synthesized in response to hormone stimulation and promotes cholesterol movement to the mitochondrial matrix would be a candidate for the acute regulation of steroidogenesis (reviewed in Stocco 2001).

StAR was first described as a 30 kDa protein in hormone-treated rat adrenal cortex and cell culture systems as a protein induced by tropic hormone stimulation. Its expression pattern was correlated with increased steroid hormone output (Krueger & Orme-Johnson 1983, Pon et al. 1986a,b, Alberta et al. 1989, Stocco & Chen 1991, Stocco & Sodeman 1991). Cloning the 30 kDa cDNA from the MA-10 mouse Leydig tumor cell line revealed a predicted protein of 284 amino acids and with no sequence similarities at either the nucleic acid or the protein level within the databases (GenEMBL and SWISS-PROT, GCG Package, University of Wisconsin) indicating, at that time, that the 30-kDa protein represented a novel protein (Clark et al. 1994). As stated above, in heterologous transient transfection experiments, expression of the cDNA-encoded 30 kDa protein resulted in an increase in steroid synthesis, and so was named the StAR (Clark et al. 1994). To date, the vast literature on StAR (herein referred to as STARD1) provides strong biochemical and genetic data that support STARD1's role in cholesterol transfer in regulated steroidogenesis (reviewed in Stocco 2001). Of particular importance was the finding that mutations in the hSTARD1 gene are the most common basis for congenital lipoid adrenal hyperplasia (lipoid CAH; Lin et al. 1995, Bose et al. 1996, King et al. 2011), a disorder characterized by the inability to synthesize adrenal or gonadal steroid hormones due to the absence of cholesterol transport into mitochondria. Recently, new mutations have been identified in the STARD1 gene that lead to partial loss of function and less severe lipoid CAH (Fluck et al. 2011). Stard1 knockout mice confirmed that in the absence of the protein, the adrenal and gonads accumulated significant lipid deposits and the animals die shortly after birth due to the absence of adrenal hormones (Caron et al. 1997). Re-expression of a Stard1 transgene in the knockout mice fully restored adrenal and gonadal steroidogenesis, as would be anticipated. However, mice that expressed an amino terminal truncated STARD1 that was not targeted to the mitochondria had partially restored steroidogenesis in a tissue- and gender-specific manner and retained lipid accumulation in the adrenal and gonads (Sasaki et al. 2008). These data support that STARD1 is capable of functioning without being targeted to the mitochondria but highlight the importance of correct and efficient subcellular localization of STARD1 for full function in vivo.

STARD1 and oxysterol production in non-steroidogenic tissues

In vitro protein overexpression studies demonstrated that STARD1 transports cholesterol across mitochondrial membranes in many cell types, potentially expanding STARD1 function outside of steroidogenic tissues (Sugawara et al. 1995). One of the first reported roles for STARD1 outside of steroidogenic cells was in cholesterol transfer across the mitochondrial membranes in the liver for initiation of bile acid synthesis by the alternative pathway. Overexpression of STARD1 significantly increases 27HC and bile acid synthesis in primary rat or mouse hepatocytes or human HepG2 hepatoma cells (Pandak et al. 2002, Ren et al. 2004a,b, Hall et al. 2005). Enhanced rates of bile acid synthesis also occur in both rats and mice after overexpression of STARD1 in the liver, providing evidence for an in vivo function (Ren et al. 2004a,b). A key finding of these studies is that the transport of cholesterol into the mitochondria is rate-limiting for bile acid synthesis by the CYP27A1 alternative pathway, suggesting that cholesterol transport into hepatic mitochondria may be regulated under normal or pathological conditions (Pandak et al. 2002). Importantly, STARD1 expression in human HepG2 hepatoma cells is increased by treatment with 27HC or by induced expression of CYP27A1, the enzyme that metabolizes cholesterol to 27HC. LXRα-dependent transactivation of Stard1 has been established in mouse adrenocortical cells (Cummins & Mangelsdorf 2006, Cummins et al. 2006). Therefore, 27HC oxysterol activation of LXRα may account for the observed increase in STARD1 in HepG2 cells. Strikingly, overexpression of Stard1 in liver of ApoE-deficient mice improved serum and liver lipid profiles and reduced lipid accumulation in aortic segments (Ning et al. 2009a,b). It has been proposed that the anti-atherogenic action of hepatic STARD1 expression is due to both increased oxysterol synthesis leading to LXR-mediated anti-atherogenic effects and increased bile acid synthesis leading to clearance of cholesterol (Ning et al. 2009a,b). Thus, mechanisms to enhance STARD1 expression in hepatocytes have been proposed as a target to help attenuate dyslipidemia and the development of atherosclerosis (Ning et al. 2009a,b). However, a potential beneficial role for STARD1 expression in hepatocytes is complicated by recent findings that show elevated STARD1 levels in liver are associated with non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (discussed below).

STARD1 overexpression in human THP-1-derived macrophages also decreases total lipid and cholesterol levels (Bai et al. 2009, Ning et al. 2009a,b). The LXRα-dependent target genes ABCG1, PPARγ, LXRα, and CYP27A1 are increased at the mRNA and protein levels in the STARD1 overexpressing cells. Treatment of THP-1 cells with the oxysterols 25HC or 27HC had similar effects on gene expression as STARD1 overexpression. These data suggest STARD1 overexpression functions in macrophages to supply cholesterol for CYP27A1-dependent oxysterol synthesis that promotes LXRα-dependent mechanism(s) to decrease cholesterol levels (Ning et al. 2009a,b). In support of this model, stable overexpression of STARD1 in RAW264.7 murine macrophages resulted in increased 27HC levels (Taylor et al. 2010). STARD1 overexpression also increased LXRα expression, LXRα-dependent reporter gene activity, ABCA1 expression, and cholesterol efflux, similar to STARD1 functioning within the LXR pathway. Suppression of the SREBP2 pathway by 27HC was indirectly indicated in these studies by decreased expression of the target genes HMGR and LDLR (Taylor et al. 2010). Interestingly, overexpression of STARD1 in THP-1 macrophage cells attenuated ox-LDL-induced inflammatory cytokine release and apoptosis (Ning et al. 2009a,b). It remains to be determined whether this effect is mediated by elevated oxysterols generated in response to STARD1 overexpression.

Detection of STARD1 protein in liver has not been consistently reported and most of the functional link to bile acid synthesis has been proposed in systems where STARD1 is exogenously supplied. Therefore, it is not clear whether endogenous STARD1 expression in the liver is sufficient to contribute significantly to bile acid synthesis via the alternative pathway. There are no reports of either bile acid disorders or increased risk for cardiovascular disease in patients with lipoid CAH who lack a functional STARD1 protein, suggesting that STARD1 is not required for liver or macrophage cholesterol metabolism. However, this does not exclude the possibility that another START protein functions in this process or that aberrant overexpression of STARD1 may occur in pathological states (see below). An important question to address is whether STARD1 levels are induced in hepatocytes and macrophages in pathological states and to determine the mechanism(s) of regulation.

STARD1 in fatty liver disease

One example for increased STARD1 expression in disease states may be in NAFLD. NAFLD describes a group of disorders associated with an accumulation of lipids, mostly triacylglycerol, in the liver. NAFLD is a common consequence of obesity and type 2 diabetes mellitus that can lead to non-alcoholic steatohepatitis (NASH) and states of hepatic fibrosis and cirrhosis. The potential for cholesterol metabolism disorders in NAFLD disease progression is suggested by reports that hepatic cholesterol accumulation enhances the progression of NAFLD to NASH in mouse models (Van Rooyen et al. 2011). A similar result appears in humans where free cholesterol levels in the liver are elevated in patients with NASH relative to patients with NAFLD or without fatty liver disease (Puri et al. 2007, Caballero et al. 2009). HMGR and SREBP2 transcript levels in liver were elevated in patients with NAFLD and NASH, providing a rationale for the elevated hepatic free cholesterol levels (Caballero et al. 2009). In this cohort, STARD1 mRNA was also increased in the liver with levels being highest in NASH patients. These data indicate a possible positive correlation between STARD1 expression and hepatic cholesterol levels, although STARD1 protein levels in the NAFLD and NASH patients remain to be measured. SREBP2 and LDLR protein levels were increased and ABC transporters were decreased in an obese, diabetic mouse model that develops NASH when on a high-fat diet (Van Rooyen et al. 2011), and the authors proposed a central role for SREBP2 in disease progression (Van Rooyen & Farrell 2011). The lipotoxicity associated with increased hepatic cholesterol levels and disease progression from NAFLD to NASH has been proposed to be mediated at the level of mitochondria (reviewed in Montero et al. (2010)). Current data indicate that mitochondria are more susceptible to apoptotic stimuli due to glutathione depletion resulting in increased reactive oxygen species levels (Mari et al. 2006). Thus, the possible positive association for STARD1 and cholesterol in NASH patients would suggest a mechanism for increased mitochondrial cholesterol content. It would be interesting to examine additional START protein family members in this disease. In particular, STARD4, which is highly expressed in hepatocytes and is regulated by SREBP2, is a strong candidate for a START protein involved in fatty liver disease (see below).

STARD1 and hepatocellular carcinoma

An increase in de novo cholesterol synthesis in hepatocellular carcinomas has been a long-standing observation (Siperstein & Fagan 1964) and only recently studies have begun to address the potential mechanism(s) for increased cholesterol synthesis in liver cancers. As with NASH, one focus has been on mitochondria with early observations that mitochondria isolated from hepatoma xenografts have increased cholesterol:phospholipid ratio relative to mitochondria from normal rat liver (Feo et al. 1973, Crain et al. 1983). Increased mitochondrial cholesterol content in cancer cells has the potential for suppression of apoptosis by decreasing mitochondrial permeability and suppressing cytochrome c release. Mitochondrial permeability is regulated by a multi-protein complex that spans the inner and outer mitochondrial membranes termed the mitochondrial permeability transition pore (mPTP; Henry-Mowatt et al. 2004). The major components of the mPTP include the voltage-dependent anion channel, the adenine nucleotide translocase, and cyclophilin D (Alirol & Martinou 2006). Apoptosis can be induced by activation of either the extrinsic or intrinsic apoptotic pathways and activation of either pathway ultimately results in caspase activation leading to cell death (Riedl & Salvesen 2007). The intrinsic apoptotic pathway involves disruption of the mPTP resulting in release of cytochrome c and pro-apoptotic proteins into the cytoplasm (Henry-Mowatt et al. 2004). Expression of pro-apoptotic BCL2 proteins, BAX and BAK, forms homo-oligomers that insert into the mitochondrial outer membrane and disrupt mPTP leading to release of cytochrome c (Cory & Adams 2002).

Elevated mitochondrial cholesterol content in hepatocellular carcinoma has recently been linked to increased STARD1 expression. Rat H35 and human HepG2 hepatoma cell lines and human hepatocellular carcinoma samples have elevated mitochondrial cholesterol content relative to cholesterol content of normal rat and human liver (Montero et al. 2008). The cholesterol levels within these cell lines correlated with an increase in SREBP2 expression (Montero et al. 2008). Blocking cholesterol synthesis in the HepG2 cells increased sensitivity to agents that induce mPTP and apoptosis, indicating a link between mitochondrial cholesterol content and chemoresistance. Cholesterol loading of isolated rat liver mitochondria increased membrane order and suppressed BAX-mediated release of cytochrome c, supporting the concept that cholesterol-enriched mitochondria are more resistant to apoptosis. STARD1 protein was highly expressed in the HepG2 cells and siRNA-mediated knockdown of STARD1 resulted in decreased mitochondrial cholesterol content and increased sensitivity to apoptosis-inducing agents. Thus, in hepatocellular carcinoma, overexpression of SREBP2 and increased cholesterol levels together with aberrant increased expression of STARD1 in the tumor may provide a mechanism for elevated mitochondrial cholesterol levels and increased resistance to apoptosis.

STARD3 and lysosomal cholesterol

STARD3/MLN64 is a transmembrane protein localized to the late endosomes by an N-terminal MENTAL (MLN64-N-terminal) domain with the C-terminal START domain facing the cytoplasm (Table 1; Tomasetto et al. 1995, Alpy et al. 2001). The location of STARD3/MLN64 to late endosomes led to studies on its potential role in Niemann Pick type C disease. Niemann Pick type C disease is a lipid storage disorder caused by mutations in genes encoding either NPC1 or NPC2 that result in accumulation of cholesterol in lysosomal storage organelles, which leads to neurological disorders and hepatosplenomegaly (reviewed in Rosenbaum & Maxfield 2011). In brief, free cholesterol that is generated by hydrolysis of LDL-derived cholesterol esters is bound by NPC2 (Niemann-Pick C2), a soluble late endosomal/lysosomal luminal protein, and transferred to the N-terminal cholesterol-binding domain of the late endosome transmembrane protein NPC1 (Niemann-Pick C1). NPC1 then transfers cholesterol across the membrane for release from the lumen by an undefined mechanism (Wang et al. 2010). The MENTAL domain of STARD3 is capable of binding cholesterol and is required for its dimerization with another endosomal membrane protein composed only of a MENTAL domain termed MENTHO (MLN64 N-terminal homolog; Alpy et al. 2005). In one model for trafficking of late endosome/lysosome cholesterol, STARD3/MLN64 acts as the cytosolic acceptor of NPC1-derived cholesterol (reviewed in Strauss et al. (2003)). Alternatively, STARD3/MLN64 and MENTHO may bind cholesterol via the MENTAL domains and independently move cholesterol across the membrane (Alpy et al. 2005, Alpy & Tomasetto 2006, Charman et al. 2009). The fate of cytosolic cholesterol bound by STARD3/MLN64 may be direct absorption by a closely associated membrane or transfer to another soluble cholesterol-binding protein, potentially a member of the STARD4 subfamily (Soccio & Breslow 2003, Alpy & Tomasetto 2006). However, it is not clear whether STARD3/MLN64 is required for cholesterol trafficking in vivo (Kishida et al. 2004). Homozygous STARD3/MLN64 mutant mice that express a STARD3/MLN64 protein containing the N-terminal MENTAL domain but lacking the START domain do not accumulate cholesterol in late endosomes/lysosomes and synthesize steroid hormones at wild-type levels (Kishida et al. 2004). Stard4, Stard5, Npc1, and Npc2 mRNA levels were not changed due to loss of the START domain from STARD3/MLN64, suggesting that the lack of a phenotype was not due to compensatory increases of these cholesterol transporters. However, whether the intact MENTAL domain of STARD3/MLN64 may be responsible for the function of this transporter in late endosomes in the knockout mice, or whether STARD4 or STARD5 can act as the soluble cytoplasmic acceptor of cholesterol from STARD3/MLN64 or NPC1, remains to be determined (Fig. 1).

STARD4 subfamily: the soluble sterol-binding proteins

The STARD4 subfamily is composed of STARD4, STARD5, and STARD6 and is most closely related to the STARD1/D3 subfamily with ∼20% sequence identity (Soccio et al. 2002; Table 1). STARD4 was identified as a novel EST in a cDNA microarray study designed to identify cholesterol-regulated genes in mouse liver (Soccio et al. 2002). Mice fed a high-cholesterol diet had reduced Stard4 transcript levels with Stard4 gene expression later shown to be regulated by a SREBP2-dependent mechanism (Soccio et al. 2002, 2005, Rodriguez-Agudo et al. 2011). STARD5 and STARD6 were identified from a BLAST search of the human genome against STARD4 (Soccio et al. 2002). Analysis of deduced amino acid sequences for the STARD4 family predicts ∼22 kDa soluble proteins entirely composed of the START domain and lacking any membrane targeting sequence (Table 1). The soluble cytoplasmic localization for these START proteins has generated much speculation on their role in cholesterol trafficking.

As outlined above, cholesterol transport to mitochondria can result in oxysterol synthesis for bile acid metabolism or LXRα-dependent responses depending on the tissue and cell type. START proteins that function to traffic cholesterol to the ER would enhance ER cholesterol that would increase ACAT activity and cholesterol ester synthesis and potentially suppress SREBP2 processing leading to decreased cholesterol synthesis. Alternatively, accumulation of cholesterol in the ER may promote ER stress. All of these endpoints have been attributed to START proteins of this subfamily; the question is which START protein plays a physiological or pathological role in which cell type and under what conditions? To explore possibilities for the role of this subfamily of START proteins in cholesterol transport, the similarities and differences between the members are reviewed with a focus on the current proposed functions.

STARD4 and cholesterol transport to the mitochondria and ER

The potential for STARD4 to deliver cholesterol to both mitochondria and ER is based on several studies where STARD4 is overexpressed in cell culture systems. Heterologous expression of STARD4 in COS-1 cells or addition of recombinant purified STARD4 to isolated mitochondria stimulated cholesterol transfer into mitochondria, although with lower efficiency relative to STARD1 (Soccio et al. 2005, Bose et al. 2008a,b). STARD4 overexpression in primary mouse hepatocytes increased bile acid synthesis and cholesterol ester synthesis (Rodriguez-Agudo et al. 2008), indicating increased cholesterol transport to mitochondria and ER (Fig. 1). Since the expression of CYP7A1, the enzyme that regulates the classical bile acid synthesis pathway, is lost in cultured primary mouse hepatocytes (Hylemon et al. 1992), these data suggest that STARD4 has the capability to increase cholesterol transport to mitochondria for the alternative pathway for bile acid synthesis. Importantly, endogenous STARD4 protein was detected in human liver by immunohistochemistry and was shown to be expressed in hepatocytes and Kupffer cells, i.e. macrophages within the liver reticuloendothelial system (Rodriguez-Agudo et al. 2011). Endogenous expression in mouse 3T3-L1 fibroblasts and human THP-1 macrophages was repressed by sterol treatment and induced by blocking cholesterol synthesis by treatment with a HMGR inhibitor. These data are consistent with a SREBP2-mediated regulation for STARD4 in vivo (Soccio et al. 2005). STARD4 colocalized with ER marker protein calnexin in 3T3-L1 cells and with ACAT1 in THP-1 macrophages, an association that was more pronounced after treatment with HMGR inhibitors to increase SREBP2-dependent increase in STARD4 (Rodriguez-Agudo et al. 2011). Cholesterol ester synthesis was increased by addition of recombinant, purified STARD4 to isolated microsomes, indicating that STARD4 positively affects ACAT activity in vitro. The association of STARD4 with ER membranes and ACAT1 and the direct effect on ACAT activity strongly support STARD4 functions to transport cholesterol to the ER and ACAT1 for cholesterol ester synthesis (Fig. 1). It remains to be determined whether STARD4-mediated cholesterol transport to the ER may also play a role in providing substrate for CYP7A1 and enhancing the classical pathway for bile acid synthesis in hepatocytes.

A role for STARD4 functioning at the ER is further supported by a recent study that demonstrated STARD4 overexpression in U2OS osteosarcoma cells enhances the transport rate of a fluorescent cholesterol analog, DHE, to the endosome recycling complex and the ER. However, the cholesterol redistribution in U2OS cells mediated by STARD4 can be mimicked with injection of the non-specific cholesterol-binding compound, methyl-β-cyclodextrin, suggesting that STARD4 may contribute to non-selective sterol transport that is required to maintain proper cholesterol distribution between cellular membranes (Mesmin et al. 2011). STARD4 overexpression also increased cholesterol ester levels and the responsiveness of SCAP-SREBP2 processing and trafficking to changes in cellular cholesterol levels (Mesmin et al. 2011). The authors propose that STARD4 represents a component of the cellular cholesterol sensing system wherein STARD4 would transport cholesterol to the ER membrane and help modulate the SREBP2 pathway and ACAT1 activity (Mesmin et al. 2011).

STARD4-mediated cholesterol transport to the ER may also promote ER stress. Although Stard4/STARD4 is established as a SREBP2 target gene (Soccio et al. 2005, Rodriguez-Agudo et al. 2011), it is also an ER stress response gene. STARD4 mRNA was increased in HeLa cells between 2 and 6 h treatment with the ER stress inducer tunicamycin and returned to control levels between 12 and 24 h (Yamada et al. 2006). Reporter gene activity assays identified an ATF6-dependent responsive element, confirming that STARD4 promoter can be activated by transcription factors that are activated during the ER stress response. The significance for the transient STARD4 mRNA expression during ER stress is not known, but an increase in STARD4 protein expression in disease states associated with dyslipidemia and ER stress may impact cholesterol homeostasis by dampening the ER cholesterol sensing system and promoting cholesterol ester formation.

Surprisingly, homozygous STARD4 knockout mice do not present with a strong lipid phenotype; the plasma and hepatic lipid content for both male and female STARD4 null mice is comparable to its wild-type counterparts (Riegelhaupt et al. 2010). However, female STARD4 knockout mice have decreased cholesterol and phospholipid content in gallbladder bile. Lipid profiles compared after 1 week on diets supplemented with high cholesterol revealed elevated plasma and hepatic lipids as expected, but the female STARD4 knockout mice had ∼20% lower plasma total cholesterol and cholesterol ester levels relative to the wild-type female mice with no differences in hepatic cholesterol, cholesterol ester, or triacylglycerol levels. There was no difference in the effect of lovastatin, a HMGR inhibitor that blocks cholesterol synthesis, on plasma or hepatic lipid profiles between the wild-type and STARD4 knockout mice. Stard5 and Stard3 mRNA expression appear to be repressed, although not significantly decreased, and Stard1 undetectable in the liver of STARD4 knockout mice, suggesting that the other major START proteins are not responsive to loss of STARD4. It remains to be determined whether environmental, dietary, or disease stressors may highlight a phenotype resulting from loss of STARD4 on cholesterol ester or bile acid synthesis.

STARD5 and cholesterol transport to the ER and PM

STARD5 does not transfer cholesterol to mitochondria in vitro (Bose et al. 2008a,b) and transient overexpression in primary mouse hepatocytes has no effect on bile acid synthesis rates (Rodriguez-Agudo et al. 2005), indicating that STARD5 does not function to transport cholesterol to mitochondria. Overexpression of human STARD5 in primary rat hepatocytes, however, resulted in increased cellular-free cholesterol levels with possible increased ER cholesterol content (Rodriguez-Agudo et al. 2005). The redistribution of cholesterol was measured as a threefold increase in cholesterol recovered with microsomes isolated from STARD5 overexpressing cells compared with controls. STARD5 binds both cholesterol and 25HC (Soccio et al. 2002, Rodriguez-Agudo et al. 2005, 2008) and is expressed predominantly in liver and kidney (Soccio et al. 2002, Chen et al. 2009). In liver, STARD5 is localized to the Kupffer cells and is not expressed in hepatocytes (Rodriguez-Agudo et al. 2006). This observation was confirmed by subcellular localization studies for STARD5 protein in cell lines from human macrophages and monocytes as well as mast, lymphoblast, and promyeloblast cells. Double immunofluorescence studies in human THP-1 macrophages revealed that STARD5 was localized to the perinuclear regions of the cell and colocalized with Golgi but not with endosome markers (Rodriguez-Agudo et al. 2006). Filipin staining to detect distribution of free cholesterol in the macrophages revealed high cholesterol concentration within the Golgi, suggesting localization of STARD5 with membranes enriched in free cholesterol. In mouse kidney sections, STARD5 protein was detected by immunohistochemistry in the proximal tubules, but not in the glomeruli (Chen et al. 2009). The staining pattern indicated diffuse cytoplasmic distribution with concentrated expression at the apical membrane. Greater resolution for STARD5 subcellular distribution by immunoelectron microscopy confirmed diffuse cytoplasmic distribution with enriched staining along the brush-border (apical) and rough ER membranes with no apparent association with mitochondria or Golgi apparatus. In HK-2 human proximal tubule cells, double immunofluorescence confocal microscopy showed that STARD5 had a punctate expression pattern that colocalizes with the ER but not endosome marker proteins. Together, the data indicate a potential broad cellular distribution, e.g. cytoplasm–PM-Golgi–ER, for STARD5 in macrophages and renal proximal tubules (Fig. 1). As a soluble sterol transporter, STARD5 may shuttle cholesterol between the Golgi, ER and PM, although STARD5's trafficking remains to be determined. However, unlike STARD4, STARD5 overexpression does not increase cholesterol ester synthesis rates (Rodriguez-Agudo et al. 2005, 2008) or ACAT activity (Rodriguez-Agudo et al. 2011), indicating a distinction for the fate of cholesterol transported to the ER by these two lipid transporters. Another distinction in overexpression systems is that STARD5 promotes an increase in free cholesterol levels while STARD4 has no effect on free cholesterol levels (Rodriguez-Agudo et al. 2005, 2008). In human proximal tubule cell lines, STARD5 expression is higher in the cells with greater cholesterol content, supporting a positive correlation between cellular free cholesterol content and STARD5 expression in the kidney (BJ Clark, unpublished observations). STARD5 overexpression in THP-1 macrophages markedly increases SREBP2 mRNA levels, suggesting a potential for increased cholesterol synthesis (Borthwick et al. 2010). Therefore, STARD5 may contribute to determining the levels of cellular free cholesterol content.

Stard5/STARD5 mRNA expression is increased by agents that promote ER stress, such as in thapsigargin-treated NIH-3T3 and HK-2 cells or cholesterol-loaded mouse macrophages (Soccio et al. 2005, Chen et al. 2009). In HK-2 human proximal tubule cells, chemically induced ER stress promotes STARD5 redistribution from a diffuse to a more prominent perinuclear and cell membrane localization (Chen et al. 2009). The role for STARD5 during ER stress is not known but chronic ER stress and inflammation are underlying metabolic disorders in many disease states, including NAFLD, type II diabetes, and cancer (Tsai & Weissman 2010, Malhi & Kaufman 2011). There is one study looking at STARD5 expression in disease states associated with ER stress. In a diabetic mouse model, Stard5 steady-state mRNA and STARD5 protein levels in kidney were shown to be significantly increased, as were free cholesterol levels, compared with wild-type control mice (Chen et al. 2009). Cholesterol accumulation in the ER is known to promote ER stress; however, the significance of the association between elevated renal cholesterol, ER stress, and STARD5 in diabetic kidney remains to be determined.

In summary, the differential regulation and distinct cell-type distribution help to control potential redundant actions of STARD4 and STARD5. STARD4 is expressed in hepatocytes and regulated by SREBP2 and activates ACAT. Therefore, in hepatocytes, STARD4 is a strong candidate for cholesterol transport to mitochondria for bile acid synthesis and to the ER for cholesterol ester synthesis. Both STARD4 and STARD5 are expressed in macrophages and both may function as cholesterol transporters that shuttle cholesterol to the ER. STARD4 would increase ACAT and cholesterol ester synthesis while STARD5 may promote an increase in free cholesterol level resulting in ER stress. Both STARD4 and STARD5, therefore, may promote foam cell development and increase the risk for atherosclerosis. Alternatively, STARD5 may serve as a cholesterol buffer to bind the free cholesterol and help suppress the potential lipotoxicity of excess free cholesterol in the cell. Similar functions proposed for STARD5 in macrophage would apply to renal proximal tubule cells. In addition, the prominent apical membrane localization in polarized epithelial cells of renal proximal tubules indicates a potential role for STARD5 in PM cholesterol (Fig. 1). Whether STARD5 contributes to lipid raft formation and stabilization or conversely, extraction of PM cholesterol remains to be determined. Finally, STARD5 binds 25HC and its role in oxysterol transport has yet to be examined.

STARD6 and cholesterol transport to the mitochondria

STARD6 was originally shown to be predominantly expressed in mouse testis and later specifically localized in rat testis to the germ cells with highest expression in round spermatids (Soccio et al. 2002, Gomes et al. 2005). The function of STARD6 in spermatogenesis is not known. However, Stard6 was recently identified as a putative gene required for mitochondrial NADH-dependent dehydrogenase activity (diaphorase) associated with sperm motility and quality (Golas et al. 2010). Using recombinant inbred mice strains, a quantitative trait loci approach identified three chromosomal regions, 19q43–19q47, 18q44, and 18q49–18q50, that segregated with diaphorase activity (Golas et al. 2010). Stard6 was highlighted as a putative gene within 18q44, leading to the speculation that Stard6 along with other genes may regulate activity of a mitochondrial enzyme. The significance of this observation may be linked to earlier work that showed addition of recombinant purified STARD6 to isolated mitochondria-stimulated cholesterol transfer as efficiently as the START domains of STARD1 and STARD3 (Bose et al. 2008a,b). Furthermore, STARD6 protein folding, cholesterol binding, and association with the mitochondrial outer membrane are all very similar to STARD1, suggesting that this protein may function at the mitochondrial level in male germ cells (Bose et al. 2008a,b). Similar to other members of the STARD4 subfamily, STARD6 lacks any organelle targeting sequence. To validate potential actions for STARD6 at the mitochondria, future studies are required to determine the subcellular localization of STARD6 in male germ cells. Expression has also been reported in rat brain and nervous system with potential regulation under neurotoxic conditions (Chang et al. 2009).

The phospholipid/sphingolipid-binding START proteins

STARD2/PCTP subfamily: the phosphatidylcholine and ceramide transporters

This subfamily is composed of STARD2, STARD7, and STARD10 that all bind phosphatidylcholine (PC) and STARD11 that binds ceramide (Table 1). STARD2/PCTP was purified from bovine liver and was shown to exchange specifically PC within a membrane or to shuttle PC from the ER to the PM. The crystal structure of STARD2 with bound PC shows the classical helix grip fold that forms a large hydrophobic tunnel. The choline head group provides the specificity of binding and the binding pocket can accommodate PC with saturated or unsaturated acyl groups of different lengths (Roderick et al. 2002).

STARD7 (also referred to as gestational trophoblastic tumor gene-1, GTT1) was first identified as a transcript that was overexpressed in JEG-3 choriocarcinoma cells (Durand et al. 2004). STARD7 shares 25% sequence identity with STARD2/PCTP and the purified protein extracts PC but not phosphatidylserine, phosphatidylethanolamine, or sphingomyelin from lipid vesicles in vitro (Horibata & Sugimoto 2010).

STARD10 was identified as a 35 kDa anti-phospho-FKHR immunoreactive band that was overexpressed in tumors of ErbB2 transgenic mice (Olayioye et al. 2004). Recombinant purified STARD10 specifically extracts PC and PE from reconstituted lipid vesicles and enhances PC and PE transfer from donor to acceptor vesicles in vitro (Olayioye et al. 2005). In vivo, PC and PE are recovered by immunoprecipitation of overexpressed STARD10 in HEK-293 cells. In both the in vitro and in vivo studies, PC appears to be the preferred lipid for STARD10 (Olayioye et al. 2005). Phosphorylation of STARD10 on Ser284 by casein kinase II decreases in vitro lipid transport activity, possibly by decreasing membrane association (Olayioye et al. 2007).

STARD11 is more commonly known as CERT, a ceramide transport protein shown to be a splice variant of the Goodpasture antigen-binding protein (GPBPΔ26). Within this subfamily, STARD2/PCTP and STARD11/CERT have been studied in more detail and have been recently reviewed by others (Kanno et al. 2007a,b, Hanada et al. 2009, Kang et al. 2010, Mencarelli et al. 2010). Therefore, only summaries of the recent data on the members of this subfamily are provided.

STARD2/PCTP and insulin resistance

The initial proposed functions for PCTP were in PC transport across the hepatic canalicular membrane and for lung surfactant synthesis, given that PC is the major phospholipid in bile and surfactant and the transporter is expressed in the hepatocytes and alveolar cells (van Helvoort et al. 1999). However, PCTP knockout mice (Pctp−/−) have no apparent phenotype with normal levels of PC measured in the bile and lung surfactant (van Helvoort et al. 1999). Although the predicted phenotype(s) was not observed with the Pctp−/− mice, new data indicate STARD2/PCTP functions in insulin-regulated pathways to maintain glucose homeostasis (Scapa et al. 2008, Shishova et al. 2011). Fasting serum glucose and free fatty acid levels are significantly decreased in Pctp−/− mice compared with wild-type counterparts due to increased insulin sensitivity (Scapa et al. 2008). In addition, hepatic SREBP1c expression is decreased in Pctp−/− mice along with downstream target gene expression for enzymes within the fatty acid biosynthesis pathway. Isolated hepatocytes from Pctp−/− mice have decreased fatty acid synthesis rates, providing a functional readout to support the gene expression profile. Treatment of wild-type mice with a STARD2/PCTP small molecular inhibitor (compound A1) that displaces PC binding attenuates high-fat diet-induced increase in serum glucose levels (Shishova et al. 2011). Treatment of human hepatocytes and HEK-293 cells with compound A1 promotes activation of the insulin signaling pathway (Shishova et al. 2011). Together, the data indicate that blocking STARD2/PCTP function in the liver results in increased hepatic insulin sensitivity. The mechanism for STARD2/PCTP action in liver glucose metabolism, however, remains to be determined.

STARD2/PCTP was recently shown to interact with thioesterase superfamily member 2 (Them2) and the transcription factor paired box gene 3 (PAX3; Kanno et al. 2007a,b). The significance of these particular protein–protein interactions is that other START family members, including mammalian STARD14 and STARD15, are multi-domain proteins that have amino-terminal thioesterase domains. In plants, a major START protein subfamily is characterized by homeobox domain(s) and function in DNA-binding and transcriptional regulation (Schrick et al. 2004). Interestingly, the thioesterase activity of recombinant Them2 in in vitro assays is enhanced by the presence of STARD2 as is the transactivation activity of PAX3 (Schrick et al. 2004). It has been speculated that during cold adaptation in mice, PCTP–Them2 interaction in brown fat increases and attenuates the uptake and oxidation of fatty acids within mitochondria (Kang et al. 2009, 2010). Although the mechanism(s) are not defined, it has been proposed that phosphorylation of STARD2/PCTP results in mitochondrial association and interaction with Them2. The PCTP–Them2 interaction increases Them2 activity resulting in a decrease in fatty acyl-CoA levels and thereby a decrease in fatty acid oxidation (Kang et al. 2009, 2010).

STARD7: a phosphatidylcholine-binding protein

A STARD7 variant, STARD7-I, was identified by a BLAST search and shown to have an extended amino terminal sequence that forms an amphipathic helix that functions as a mitochondrial targeting sequence (Horibata & Sugimoto 2010). Mitochondrial PC levels in the HEPA-1 mouse hepatoma cell line are increased after STARD7 overexpression but are unchanged by STARD7 silencing by siRNA. STARD7-I can be processed to a smaller protein, presumably by mitochondrial proteases that cleave the targeting sequence, but it remains sensitive to protease digestion when isolated mitochondria are treated with proteinase K (Horibata & Sugimoto 2010). Thus, STARD7 appears to remain on the cytoplasmic side of the mitochondrial outer membrane. This membrane association would be consistent with both the cytosolic and mitochondrial localization of endogenous STARD7-I in the HEPA-1 mouse hepatoma cell line and rat liver. Regulating mitochondrial PC levels would influence membrane structure and, as the authors of this study speculate, regulate acylation reactions (Horibata & Sugimoto 2010). Since STARD7 is expressed at relatively high levels in lung, colon, and liver cancer cell lines (Durand et al. 2004), it may play a more general role in proliferating cells, possibly for supply of PC for mitochondrial biogenesis.

STARD10: a phosphatidylcholine/ethanolamine-binding protein in breast cancer

STARD10 was originally reported to be co-expressed with ErbB2/HER2/neu in breast cancer cell lines and primary breast carcinomas (Olayioye et al. 2004). Functionally, the overexpression of STARD10 in NIH-3T3 fibroblast cells promoted anchorage-independent cell growth only if expressed together with ErbB2, suggesting that STARD10 may function within the ErbB2/HER2/neu receptor signaling pathway (Olayioye et al. 2004). However, STARD10 and HER2/neu mRNA and protein expression levels were later shown to be inversely correlated when analyzed in breast tumors from a large cohort of patients (Murphy et al. 2009). Unexpectedly, loss of STARD10 expression was found to be an independent marker for poor patient outcome and may be used to identify a specific subgroup of patients at high risk (Murphy et al. 2009). Whether the beneficial effect for STARD10 expression in breast cancer is related to its PC binding/transport activity will require elucidating the biological functions of STARD10 in mammary tissues (Olayioye et al. 2005). This function most likely will be related to the phosphorylation state of STARD10, therefore elucidating the phosphatase(s) responsible for the dephosphorylation and activation of STARD10, and the pathways involved in STARD10 activation are important future studies (Olayioye et al. 2007).

STARD11/CERT: a ceramide-binding protein

STARD11 is unique within this subfamily in that the protein contains additional motifs that localize the START domain to its cellular sites of action. STARD11/CERT is responsible for the movement of ceramide from the ER to the Golgi membrane (Hanada et al. 2003). The protein has an amino terminal pleckstrin homology domain (PH), a middle region with a FFAT motif, and carboxyl terminal START domain (Table 1). The PH domain binds to phosphoinositides, specifically PI4P in the Golgi membrane, while the FFAT motif interacts with the ER resident protein VAP. STARD11/CERT phosphorylation is proposed to maintain the protein in a folded, inactive form with dephosphorylation resulting in a conformational change that exposes the PH and FFAT domains for membrane interaction and positions the START domain for ceramide transfer. A detailed description of the proposed model for ceramide transfer by STARD11/CERT has been presented (Hanada et al. 2009) and the basic concept is the orientation of the protein with the N-terminus bound to the Golgi membrane and the middle region bound to the ER would place the START domain in close proximity to both membranes to facilitate ceramide extraction from the ER and delivery to the Golgi. The crystal structure of the STARD11/CERT START domain confirmed the helix-grip fold structure for ceramide binding and supports a mechanism for membrane interaction and ceramide extraction/absorption (Kudo et al. 2008, 2010).

The multi-domain START proteins

STARD8/12/13: the SAM-RhoGAP-START subfamily

This subfamily is more commonly referred to as the deleted in liver cancer (DLC) family of proteins. The history, genomic structure, isoform expression, and known and potential function(s) for STARD12/DLC-1, STARD13/DLC-2, and STARD8/DLC-3 have been reviewed (Durkin et al. 2007a,b) and only a few aspects are highlighted here. Members of this subfamily share the same multi-domain structure, an amino terminal sterile α motif (SAM; Ponting 1995) followed by a serine-rich region, a RhoGAP domain, and a carboxyl-terminal START domain (Table 1). STARD12/DLC-1 was first isolated as a genomic clone that was localized on chromosome 8p21.3–22, a region associated with loss of heterozygosity in several cancers and shown to be deleted in 50% of primary human hepatocellular carcinoma tumor tissues (Yuan et al. 1998). Re-expression of DLC-1 in human liver, lung, breast, and ovarian cancer cell lines suppresses cell growth and increases apoptosis, supporting DLC-1 as a tumor suppressor. Protein kinase D phosphorylates multiple sites on STAR12/DLC-1 and the phosphoprotein has decreased activity (Scholz et al. 2009, 2011), suggesting a potential regulatory mechanism controlling STARD12/DLC-1 function. Targeted deletion of Stard12/dlc-1 gene in mice results in embryonic lethality, most likely due to disruption of cytoskeletal organization. STARD12/DLC-1 has been shown to regulate RhoA activity via the RhoGAP domain, to colocalize with focal adhesions via binding to the SH2 domain of tensin 1, and to stimulate PLC-δ1 leading to IP3-dependent intracellular Ca2+ release (Durkin et al. 2007a,b). Any or all of these functions could disrupt/promote cytoskeletal organization.

STARD13/DLC-2 and STARD8/DLC-3 also have tumor suppressor activities when overexpressed in cancer cell lines (Ching et al. 2003, Durkin et al. 2007a,b) and localize to focal adhesions (Kawai et al. 2007, 2009), indicating similar activities as characterized for STARD12/DLC-1. However, STARD13/DLC-2 and STARD8/DLC-3 cannot compensate for loss of STARD12/DLC-1. Recent reports characterizing STARD13/DLC-2 knockout mice show that the mice are healthy and fertile with no overt phenotype (Yau et al. 2009, Lin et al. 2010). The knockout mice were not more susceptible to spontaneous tumors or induced hepatocarcinogenesis, indicating potential compensatory effects of the other DLCs for tumor suppressor activity or possible requirement for a ‘second hit’ to promote tumor formation (Yau et al. 2009, Lin et al. 2010). However, STARD13/DLC-2 may help suppress angiogenesis associated with tumor growth (Lin et al. 2010). STARD13/DLC-2 has widespread tissue distribution, with expression observed in CD31-positive cells of blood vessels, indicating endothelial specific expression. Based on this observation, matrigel-induced vascularization and B16 murine melanoma xenograft tumor cell growth assays were performed and angiogenesis was shown to be enhanced in the knockout mice compared with wild-type counterparts. Silencing STARD12/DLC-2 expression in HUVECs leads to increased cell migration in a RhoA-dependent manner, supporting the in vivo data for STARD12/DLC-2 promoting angiogenesis (Lin et al. 2010).

To date, the functions associated with this subfamily have been attributed to the RhoGAP domain. The role of the START domain in these proteins is not known. However, confocal fluorescent imaging demonstrated that endogenous STARD12/DLC-1 colocalizes with caveolin-1 in BHK cells and the two proteins co-immunoprecipitated, indicating that STARD12/DLC-1 is localized to cholesterol and sphingolipid-rich regions of the PM (Yamaga et al. 2004). The caveolin-1 interaction is dependent on the RhoGAP domain of STARD12/DLC-1 and the authors of this study speculated that the START domain may bind cholesterol and regulate STARD12/DLC-1 GAP function (Yamaga et al. 2004). Expression of a tagged STARD13/DLC-2 in a human hepatoma cell line was shown by confocal immunofluorescence imaging to be localized with mitochondria (Ng et al. 2006) and the mitochondrial association was dependent on the START domain. Expression of the START domain of STARD12/DLC-1 in a breast cancer cell line, on the other hand, did not show a pattern consistent with mitochondrial localization and the full protein was localized to the cytoskeleton and enriched at focal adhesions (Kim et al. 2008). The ligand(s) that bind the START domain(s) of this subfamily remain to be determined. New data on the crystal structure for STARD13/DLC-2, however, indicate that the STARD13/DLC-2 ligand-binding pocket is smaller and contains polar residues that make it different from the cholesterol and phospholipid START proteins. The authors propose that a charged lipid would be a likely binding candidate (Thorsell et al. 2011). Once the START domain ligands have been defined, this information will help to elucidate the biological significance for the START domain within this family of RhoGAP proteins. It will be interesting to see the effect of the lipid binding to the START domain on RhoGAP activity and whether subcellular localization and/or ligand binding affects function.

STARD14/15: the acyl-CoA thioesterase subfamily.

The acyl-coenzyme A thioesterase (ACOT) family of proteins hydrolyze the thioester bond of fatty acyl-CoAs to generate free fatty acids and coenzyme A (reviewed in Kirkby et al. (2010)). ACOT11_v2 and ACOT12 are unique within this family as they contain C-terminal START domains (Hunt et al. 2005, Kirkby et al. 2010) and are also known as STARD14 and STARD15 respectively (SRPBCC protein superfamily on NCBI's Conserved Domain Database). Human STARD14/ACOT11_v2 is a splice variant that is the ortholog of the mouse brown fat-inducible thioesterase (mBFIT2; Adams et al. 2001; Table 1). mBFIT2 is induced in brown adipose tissue of mice after exposure to cold temperatures and is expressed at higher levels in lean mouse models compared with obese mouse models. The data suggest an association between STARD14/ACOT11_v2/BFIT2 with increased metabolic activity in brown fat. STARD15/ACOT12 is a cytosolic acetyl-CoA thioesterase (hydrolase) that has been cloned from rat, mouse, and human (Suematsu et al. 2001, 2002, Suematsu & Isohashi 2006) and is highly expressed in liver. The biological significance for the thioesterase activity of this enzyme should be implicit based on the fact that acetyl-CoA is the substrate, but this enzyme has been relatively understudied.

The crystal structure for the START domain of STARD14/ACOT11_v2/BFIT2 shows that the functionally critical C-terminal α helix is broken into two shorter helices (Thorsell et al. 2011). Electron density consistent with a fatty acid filled the ligand-binding cavity in the crystal, but the actual ligand and whether it is a fatty acid was not solved. It is tempting to speculate that fatty acid binding may regulate thioesterase activity of these enzymes; possibly, the START domain binds the free fatty acid product for transfer to fatty acid binding proteins, the soluble intracellular carriers of fatty acids.

Summary

One-third of the mammalian START domain proteins belong to the STARD1/D3 and STARD4 subfamilies and function to bind and transport cholesterol and oxysterols. While the biological function of STARD1 is established as the regulator of cholesterol transport across mitochondrial membranes for steroid hormone synthesis, the challenge remains to define the functions for the remaining members of the cholesterol-binding proteins. Current data suggest that both STARD4 and STARD5 associate with ER cholesterol yet serve unique roles at the ER membrane. The knockout mouse models that do not present with an apparent phenotype will require further study to determine whether exposure to environmental, dietary, or disease stressors may highlight a phenotype associated with loss of the START protein(s). Alternatively, a phenotype may only manifest upon aberrant overexpression of a START protein, as indicated by the studies that demonstrate overexpression of START proteins leads to disorders in cholesterol homeostasis in hepatocytes and macrophages. Therefore, it will be important to continue to identify START protein expression associated with different disease states that involve dyslipidemia, inflammation, and ER stress to help establish the biological significance of the in vitro data and to help distinguish unique functions from redundant functions for the STARD4 subfamily.

The phospholipid/sphingolipid-binding proteins of the STARD2/PCTP subfamily appear to have diverse functions, from modulating insulin sensitivity in liver to inter-membrane transfer of ceramide, and tumor proliferation. Although the ligands are known for this subfamily, it is not yet clear what the significance is for phosphatidylcholine binding. Similarly, the next question to address for the RhoGAP and thioesterase START protein subfamilies is whether lipid binding within the START domain affects the function of the protein. The first step, however, is to determine the ligands that bind to the START domains of members of these two subfamilies.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This review was supported in part by grants from The Kentucky Lung Cancer Research Program and University of Louisville, School of Medicine, Office of the Executive VP for Health Affairs Research Program.

Acknowledgements

The author thanks Drs William L Dean, Steven R Ellis, and Carolyn M Klinge, Department of Biochemistry and Molecular Biology, University of Louisville, for their critical reading of the manuscript.

References

  • Adams SH, Chui C, Schilbach SL, Yu XX, Goddard AD, Grimaldi JC, Lee J, Dowd P, Colman S & Lewin DA 2001 BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity. Biochemical Journal 360 135142. doi:10.1042/0264-6021:3600135.

    • Search Google Scholar
    • Export Citation
  • Alberta JA, Epstein LF, Pon LA & Orme-Johnson NR 1989 Mitochondrial localization of a phosphoprotein that rapidly accumulates in adrenal cortex cells exposed to adrenocorticotropic hormone or to cAMP. Journal of Biological Chemistry 264 23682372.

    • Search Google Scholar
    • Export Citation
  • Alirol E & Martinou JC 2006 Mitochondria and cancer: is there a morphological connection? Oncogene 25 47064716. doi:10.1038/sj.onc.1209600.

  • Alpy F & Tomasetto C 2005 Give lipids a START: the StAR-related lipid transfer (START) domain in mammals. Journal of Cell Science 118 27912801. doi:10.1242/jcs.02485.

    • Search Google Scholar
    • Export Citation
  • Alpy F & Tomasetto C 2006 MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochemical Society Transactions 34 343345. doi:10.1042/BST0340343.

    • Search Google Scholar
    • Export Citation
  • Alpy F, Stoeckel ME, Dierich A, Escola JM, Wendling C, Chenard MP, Vanier MT, Gruenberg J, Tomasetto C & Rio MC 2001 The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. Journal of Biological Chemistry 276 42614269. doi:10.1074/jbc.M006279200.

    • Search Google Scholar
    • Export Citation
  • Alpy F, Latchumanan VK, Kedinger V, Janoshazi A, Thiele C, Wendling C, Rio MC & Tomasetto C 2005 Functional characterization of the MENTAL domain. Journal of Biological Chemistry 280 1794517952. doi:10.1074/jbc.M500723200.

    • Search Google Scholar
    • Export Citation
  • Anderson RGW 2003 Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends in Cell Biology 13 534539. doi:10.1016/j.tcb.2003.08.007.

    • Search Google Scholar
    • Export Citation
  • Arakane F, Sugawara T, Nishino H, Liu Z, Holt JA, Pain D, Stocco DM, Miller WL & Strauss JF III 1996 Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action. PNAS 93 1373113736. doi:10.1073/pnas.93.24.13731.

    • Search Google Scholar
    • Export Citation
  • Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM & Strauss JF III 1997 Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. Journal of Biological Chemistry 272 3265632662. doi:10.1074/jbc.272.51.32656.

    • Search Google Scholar
    • Export Citation
  • Arakane F, Kallen CB, Watari H, Foster JA, Sepuri NB, Pain D, Stayrook SE, Lewis M, Gerton GL & Strauss JF III 1998 The mechanism of action of steroidogenic acute regulatory protein (StAR). StAR acts on the outside of mitochondria to stimulate steroidogenesis. Journal of Biological Chemistry 273 1633916345. doi:10.1074/jbc.273.26.16339.

    • Search Google Scholar
    • Export Citation
  • Artemenko IP, Zhao D, Hales DB, Hales KH & Jefcoate CR 2001 Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells. Journal of Biological Chemistry 276 4658346596. doi:10.1074/jbc.M107815200.

    • Search Google Scholar
    • Export Citation
  • Babiker A & Diczfalusy U 1998 Transport of side-chain oxidized oxysterols in the human circulation. Biochimica et Biophysica Acta 1392 333339. doi:10.1016/S0005-2760(98)00047-2.

    • Search Google Scholar
    • Export Citation
  • Bai Q, Li X, Ning Y, Zhao F & Yin L 2009 Mitochondrial cholesterol transporter, StAR, inhibits human THP-1 monocyte-derived macrophage apoptosis. Lipids 45 2936. doi:10.1007/s11745-009-3375-6.

    • Search Google Scholar
    • Export Citation
  • Baker BY, Yaworsky DC & Miller WL 2005 A pH-dependent molten globule transition is required for activity of the steroidogenic acute regulatory protein, StAR. Journal of Biological Chemistry 280 4175341760. doi:10.1074/jbc.M510241200.

    • Search Google Scholar
    • Export Citation
  • Baker BY, Epand RF, Epand RM & Miller WL 2007 Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR. Journal of Biological Chemistry 282 1022310232. doi:10.1074/jbc.M611221200.

    • Search Google Scholar
    • Export Citation
  • Barbar E, Lavigne P & Lehoux JG 2009 Validation of the mechanism of cholesterol binding by StAR using short molecular dynamics simulations. Journal of Steroid Biochemistry and Molecular Biology 113 9297. doi:10.1016/j.jsbmb.2008.11.008.

    • Search Google Scholar
    • Export Citation
  • Bjorkhem I, Diczfalusy U & Lutjohann D 1999 Removal of cholesterol from extrahepatic sources by oxidative mechanisms. Current Opinion in Lipidology 10 161165. doi:10.1097/00041433-199904000-00010.

    • Search Google Scholar
    • Export Citation
  • Borthwick F, Allen AM, Taylor JM & Graham A 2010 Overexpression of STARD3 in human monocyte/macrophages induces an anti-atherogenic lipid phenotype. Clinical Science 119 265272. doi:10.1042/CS20100266.

    • Search Google Scholar
    • Export Citation
  • Bose HS, Sugawara T, Strauss JF III & Miller WL 1996 The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. New England Journal of Medicine 335 18701878. doi:10.1056/NEJM199612193352503.

    • Search Google Scholar
    • Export Citation
  • Bose HS, Whittal RM, Baldwin MA & Miller WL 1999 The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. PNAS 96 72507255. doi:10.1073/pnas.96.13.7250.

    • Search Google Scholar
    • Export Citation
  • Bose H, Lingappa VR & Miller WL 2002 Rapid regulation of steroidogenesis by mitochondrial protein import. Nature 417 8791. doi:10.1038/417087a.

  • Bose HS, Whittal RM, Ran Y, Bose M, Baker BY & Miller WL 2008a StAR-like activity and molten globule behavior of StARD6, a male germ-line protein. Biochemistry 47 22772288. doi:10.1021/bi701966a.

    • Search Google Scholar
    • Export Citation
  • Bose M, Whittal RM, Miller WL & Bose HS 2008b Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein. Journal of Biological Chemistry 283 88378845. doi:10.1074/jbc.M709221200.

    • Search Google Scholar
    • Export Citation
  • Brown MS & Goldstein JL 2009 Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL. Journal of Lipid Research 50 (Suppl) S15S27. doi:10.1194/jlr.R800054-JLR200.

    • Search Google Scholar
    • Export Citation
  • Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J & Garcia-Ruiz C 2009 Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. Journal of Hepatology 50 789796. doi:10.1016/j.jhep.2008.12.016.

    • Search Google Scholar
    • Export Citation
  • Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ & Parker KL 1997 Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. PNAS 94 1154011545. doi:10.1073/pnas.94.21.11540.

    • Search Google Scholar
    • Export Citation
  • Chang IY, Kim JK, Lee SM, Kim JN, Soh J, Kim JW & Yoon SP 2009 The changed immunoreactivity of StarD6 after pilocarpine-induced epilepsy. Neuroreport 20 963967. doi:10.1097/WNR.0b013e32832ca264.

    • Search Google Scholar
    • Export Citation
  • Charman M, Kennedy BE, Osborne N & Karten B 2009 MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. Journal of Lipid Research 51 10231034. doi:10.1194/jlr.M002345.

    • Search Google Scholar
    • Export Citation
  • Chen Y-C, Meier RK, Zheng S, Khundmiri SJ, Tseng MT, Lederer ED, Epstein PN & Clark BJ 2009 Steroidogenic acute regulatory (StAR)-related lipid transfer domain protein 5 (STARD5) localization and regulation in renal tubules. American Journal of Physiology. Renal Physiology 297 F380F388. doi:10.1152/ajprenal.90433.2008.

    • Search Google Scholar
    • Export Citation
  • Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY & Ng IO 2003 Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. Journal of Biological Chemistry 278 1082410830. doi:10.1074/jbc.M208310200.

    • Search Google Scholar
    • Export Citation
  • Christenson LK & Strauss JF III 2001 Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action. Archives of Medical Research 32 576586. doi:10.1016/S0188-4409(01)00338-1.

    • Search Google Scholar
    • Export Citation
  • Clark BJ, Wells J, King SR & Stocco DM 1994 The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). Journal of Biological Chemistry 269 2831428322.

    • Search Google Scholar
    • Export Citation
  • Cory S & Adams JM 2002 The Bcl2 family: regulators of the cellular life-or-death switch. Nature Reviews. Cancer 2 647656. doi:10.1038/nrc883.

  • Crain RC, Clark RW & Harvey BE 1983 Role of lipid transfer proteins in the abnormal lipid content of Morris hepatoma mitochondria and microsomes. Cancer Research 43 31973202.

    • Search Google Scholar
    • Export Citation
  • Cummins CL & Mangelsdorf DJ 2006 Liver X receptors and cholesterol homoeostasis: spotlight on the adrenal gland. Biochemical Society Transactions 34 11101113. doi:10.1042/BST0341110.

    • Search Google Scholar
    • Export Citation
  • Cummins CL, Volle DH, Zhang Y, McDonald JG, Sion B, Lefrançois-Martinez A-M, Caira F, Veyssière G, Mangelsdorf DJ & Lobaccaro J-MA 2006 Liver X receptors regulate adrenal cholesterol balance. Journal of Clinical Investigation 116 19021912. doi:10.1172/JCI28400.

    • Search Google Scholar
    • Export Citation
  • Danielsen EM & Hansen GH 2003 Lipid rafts in epithelial brush borders: atypical membrane microdomains with specialized functions. Biochimica et Biophysica Acta 1617 19. doi:10.1016/j.bbamem.2003.09.005.

    • Search Google Scholar
    • Export Citation
  • Durand S, Angeletti S & Genti-Raimondi S 2004 GTT1/StarD7, a novel phosphatidylcholine transfer protein-like highly expressed in gestational trophoblastic tumour: cloning and characterization. Placenta 25 3744. doi:10.1016/S0143-4004(03)00214-5.

    • Search Google Scholar
    • Export Citation
  • Durkin ME, Ullmannova V, Guan M & Popescu NC 2007a Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth. Oncogene 26 45804589. doi:10.1038/sj.onc.1210244.

    • Search Google Scholar
    • Export Citation
  • Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS & Popescu NC 2007b DLC-1:a Rho GTPase-activating protein and tumour suppressor. Journal of Cellular and Molecular Medicine 11 11851207. doi:10.1111/j.1582-4934.2007.00098.x.

    • Search Google Scholar
    • Export Citation
  • Dyson MT, Jones JK, Kowalewski MP, Manna PR, Alonso M, Gottesman ME & Stocco DM 2008 Mitochondrial A-kinase anchoring protein 121 binds type II protein kinase A and enhances steroidogenic acute regulatory protein-mediated steroidogenesis in MA-10 mouse Leydig tumor cells. Biology of Reproduction 78 267277. doi:10.1095/biolreprod.107.064238.

    • Search Google Scholar
    • Export Citation
  • Feo F, Canuto RA, Bertone G, Garcea R & Pani P 1973 Cholesterol and phospholipid composition of mitochondria and microsomes isolated from morris hepatoma 5123 and rat liver. FEBS Letters 33 229232. doi:10.1016/0014-5793(73)80199-1.

    • Search Google Scholar
    • Export Citation
  • Fleury A, Mathieu AP, Ducharme L, Hales DB & LeHoux JG 2004 Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR). Journal of Steroid Biochemistry and Molecular Biology 91 259271. doi:10.1016/j.jsbmb.2004.04.010.

    • Search Google Scholar
    • Export Citation
  • Fluck CE, Pandey AV, Dick B, Camats N, Fernandez-Cancio M, Clemente M, Gussinye M, Carrascosa A, Mullis PE & Audi L 2011 Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia. PLoS ONE 6 e20178 doi:10.1371/journal.pone.0020178.

    • Search Google Scholar
    • Export Citation
  • Golas A, Malek P, Piasecka M & Styrna J 2010 Sperm mitochondria diaphorase activity – a gene mapping study of recombinant inbred strains of mice. International Journal of Developmental Biology 54 667673. doi:10.1387/ijdb.082778ag.

    • Search Google Scholar
    • Export Citation
  • Goldstein JL & Brown MS 2009 The LDL receptor. Arteriosclerosis, Thrombosis, and Vascular Biology 29 431438. doi:10.1161/ATVBAHA.108.179564.

  • Gomes C, Oh SD, Kim JW, Chun SY, Lee K, Kwon HB & Soh J 2005 Expression of the putative sterol binding protein Stard6 gene is male germ cell specific. Biology of Reproduction 72 651658. doi:10.1095/biolreprod.104.032672.

    • Search Google Scholar
    • Export Citation
  • Hall EA, Ren S, Hylemon PB, Rodriguez-Agudo D, Redford K, Marques D, Kang D, Gil G & Pandak WM 2005 Detection of the steroidogenic acute regulatory protein, StAR, in human liver cells. Biochimica et Biophysica Acta 1733 111119. doi:10.1016/j.bbalip.2005.01.004.

    • Search Google Scholar
    • Export Citation
  • Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M & Nishijima M 2003 Molecular machinery for non-vesicular trafficking of ceramide. Nature 426 803809. doi:10.1038/nature02188.

    • Search Google Scholar
    • Export Citation
  • Hanada K, Kumagai K, Tomishige N & Yamaji T 2009 CERT-mediated trafficking of ceramide. Biochimica et Biophysica Acta 1791 684691. doi:10.1016/j.bbalip.2009.01.006.

    • Search Google Scholar
    • Export Citation
  • Hanzal-Bayer MF & Hancock JF 2007 Lipid rafts and membrane traffic. FEBS Letters 581 20982104. doi:10.1016/j.febslet.2007.03.019.

  • Hauet T, Yao ZX, Bose HS, Wall CT, Han Z, Li W, Hales DB, Miller WL, Culty M & Papadopoulos V 2005 Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into Leydig cell mitochondria. Molecular Endocrinology 19 540554. doi:10.1210/me.2004-0307.

    • Search Google Scholar
    • Export Citation
  • van Helvoort A, de Brouwer A, Ottenhoff R, Brouwers JF, Wijnholds J, Beijnen JH, Rijneveld A, van der Poll T, van der Valk MA & Majoor D 1999 Mice without phosphatidylcholine transfer protein have no defects in the secretion of phosphatidylcholine into bile or into lung airspaces. PNAS 96 1150111506. doi:10.1073/pnas.96.20.11501.

    • Search Google Scholar
    • Export Citation
  • Henry-Mowatt J, Dive C, Martinou JC & James D 2004 Role of mitochondrial membrane permeabilization in apoptosis and cancer. Oncogene 23 28502860. doi:10.1038/sj.onc.1207534.

    • Search Google Scholar
    • Export Citation
  • Horibata Y & Sugimoto H 2010 StarD7 mediates the intracellular trafficking of phosphatidylcholine to mitochondria. Journal of Biological Chemistry 285 73587365. doi:10.1074/jbc.M109.056960.

    • Search Google Scholar
    • Export Citation
  • Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS & Goldstein JL 2003 Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. PNAS 100 1202712032. doi:10.1073/pnas.1534923100.

    • Search Google Scholar
    • Export Citation
  • Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL & Wang X 1993 SREBP-2, a second basic-helix–loop–helix–leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. PNAS 90 1160311607. doi:10.1073/pnas.90.24.11603.

    • Search Google Scholar
    • Export Citation
  • Hunt MC, Yamada J, Maltais LJ, Wright MW, Podesta EJ & Alexson SE 2005 A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases. Journal of Lipid Research 46 20292032. doi:10.1194/jlr.E500003-JLR200.

    • Search Google Scholar
    • Export Citation
  • Hylemon PB, Gurley EC, Stravitz RT, Litz JS, Pandak WM, Chiang JY & Vlahcevic ZR 1992 Hormonal regulation of cholesterol 7 alpha-hydroxylase mRNA levels and transcriptional activity in primary rat hepatocyte cultures. Journal of Biological Chemistry 267 1686616871.

    • Search Google Scholar
    • Export Citation
  • Iyer LM, Koonin EV & Aravind L 2001 Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily. Proteins 43 134144. doi:10.1002/1097-0134(20010501)43:2<134::AID-PROT1025>3.0.CO;2-I.

    • Search Google Scholar
    • Export Citation
  • Jo Y, King SR, Khan SA & Stocco DM 2005 Involvement of protein kinase C and cyclic adenosine 3′,5′-monophosphate-dependent kinase in steroidogenic acute regulatory protein expression and steroid biosynthesis in Leydig cells. Biology of Reproduction 73 244255. doi:10.1095/biolreprod.104.037721.

    • Search Google Scholar
    • Export Citation
  • Kang HW, Ribich S, Kim BW, Hagen SJ, Bianco AC & Cohen DE 2009 Mice lacking Pctp/StarD2 exhibit increased adaptive thermogenesis and enlarged mitochondria in brown adipose tissue. Journal of Lipid Research 50 22122221. doi:10.1194/jlr.M900013-JLR200.

    • Search Google Scholar
    • Export Citation
  • Kang HW, Wei J & Cohen DE 2010 PC-TP/StARD2: of membranes and metabolism. Trends in Endocrinology and Metabolism 21 449456. doi:10.1016/j.tem.2010.02.001.

    • Search Google Scholar
    • Export Citation
  • Kanno K, Wu MK, Agate DS, Fanelli BJ, Wagle N, Scapa EF, Ukomadu C & Cohen DE 2007a Interacting proteins dictate function of the minimal START domain phosphatidylcholine transfer protein/StarD2. Journal of Biological Chemistry 282 3072830736. doi:10.1074/jbc.M703745200.

    • Search Google Scholar
    • Export Citation
  • Kanno K, Wu MK, Scapa EF, Roderick SL & Cohen DE 2007b Structure and function of phosphatidylcholine transfer protein (PC-TP)/StarD2. Biochimica et Biophysica Acta 1771 654662. doi:10.1016/j.bbalip.2007.04.003.

    • Search Google Scholar
    • Export Citation
  • Kawai K, Kiyota M, Seike J, Deki Y & Yagisawa H 2007 START-GAP3/DLC3 is a GAP for RhoA and Cdc42 and is localized in focal adhesions regulating cell morphology. Biochemical and Biophysical Research Communications 364 783789. doi:10.1016/j.bbrc.2007.10.052.

    • Search Google Scholar
    • Export Citation
  • Kawai K, Seike J, Iino T, Kiyota M, Iwamae Y, Nishitani H & Yagisawa H 2009 START-GAP2/DLC2 is localized in focal adhesions via its N-terminal region. Biochemical and Biophysical Research Communications 380 736741. doi:10.1016/j.bbrc.2009.01.095.

    • Search Google Scholar
    • Export Citation
  • Kim TY, Healy KD, Der CJ, Sciaky N, Bang YJ & Juliano RL 2008 Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration. Journal of Biological Chemistry 283 3276232770. doi:10.1074/jbc.M800617200.

    • Search Google Scholar
    • Export Citation
  • King SR, Bhangoo A & Stocco DM 2011 Functional and physiological consequences of StAR deficiency: role in lipoid congenital adrenal hyperplasia. Endocrine Development 20 4753. doi:10.1159/000321214.

    • Search Google Scholar
    • Export Citation
  • Kirkby B, Roman N, Kobe B, Kellie S & Forwood JK 2010 Functional and structural properties of mammalian acyl-coenzyme A thioesterases. Progress in Lipid Research 49 366377. doi:10.1016/j.plipres.2010.04.001.

    • Search Google Scholar
    • Export Citation
  • Kishida T, Kostetskii I, Zhang Z, Martinez F, Liu P, Walkley SU, Dwyer NK, Blanchette-Mackie EJ, Radice GL & Strauss JF III 2004 Targeted mutation of the MLN64 START domain causes only modest alterations in cellular sterol metabolism. Journal of Biological Chemistry 279 1927619285. doi:10.1074/jbc.M400717200.

    • Search Google Scholar
    • Export Citation
  • Krueger RJ & Orme-Johnson NR 1983 Acute adrenocorticotropic hormone stimulation of adrenal corticosteroidogenesis. Discovery of a rapidly induced protein. Journal of Biological Chemistry 258 1015910167.

    • Search Google Scholar
    • Export Citation
  • Kudo N, Kumagai K, Tomishige N, Yamaji T, Wakatsuki S, Nishijima M, Hanada K & Kato R 2008 Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. PNAS 105 488493. doi:10.1073/pnas.0709191105.

    • Search Google Scholar
    • Export Citation
  • Kudo N, Kumagai K, Matsubara R, Kobayashi S, Hanada K, Wakatsuki S & Kato R 2010 Crystal structures of the CERT START domain with inhibitors provide insights into the mechanism of ceramide transfer. Journal of Molecular Biology 396 245251. doi:10.1016/j.jmb.2009.12.029.

    • Search Google Scholar
    • Export Citation
  • Lavigne P, Najmanivich R & Lehoux JG 2010 Mammalian StAR-related lipid transfer (START) domains with specificity for cholesterol: structural conservation and mechanism of reversible binding. Sub-Cellular Biochemistry 51 425437. doi:10.1007/978-90-481-8622-8_15.

    • Search Google Scholar
    • Export Citation
  • Lev S 2010 Non-vesicular lipid transport by lipid-transfer proteins and beyond. Nature Review. Molecular and Cellular Biology 11 739750. doi:10.1038/nrm2971.

    • Search Google Scholar
    • Export Citation
  • Li X, Pandak WM, Erickson SK, Ma Y, Yin L, Hylemon P & Ren S 2007 Biosynthesis of the regulatory oxysterol, 5-cholesten-3beta,25-diol 3-sulfate, in hepatocytes. Journal of Lipid Research 48 25872596. doi:10.1194/jlr.M700301-JLR200.

    • Search Google Scholar
    • Export Citation
  • Lin D, Sugawara T, Strauss JF III, Clark BJ, Stocco DM, Saenger P, Rogol A & Miller WL 1995 Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267 18281831. doi:10.1126/science.7892608.

    • Search Google Scholar
    • Export Citation
  • Lin Y, Chen NT, Shih YP, Liao YC, Xue L & Lo SH 2010 DLC2 modulates angiogenic responses in vascular endothelial cells by regulating cell attachment and migration. Oncogene 29 30103016. doi:10.1038/onc.2010.54.

    • Search Google Scholar
    • Export Citation
  • Lingwood D & Simons K 2010 Lipid rafts as a membrane-organizing principle. Science 327 4650. doi:10.1126/science.1174621.

  • Malhi H & Kaufman RJ 2011 Endoplasmic reticulum stress in liver disease. Journal of Hepatology 54 795809. doi:10.1016/j.jhep.2010.11.005.

  • Marchler-Bauer A, Anderson JB, Chitsaz F, Derbyshire MK, DeWeese-Scott C, Fong JH, Geer LY, Geer RC, Gonzales NR & Gwadz M 2009 CDD: specific functional annotation with the conserved domain database. Nucleic Acids Research 37 D205D210. doi:10.1093/nar/gkn845.

    • Search Google Scholar
    • Export Citation
  • Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, Enrich C, Fernandez-Checa JC & Garcia-Ruiz C 2006 Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metabolism 4 185198. doi:10.1016/j.cmet.2006.07.006.

    • Search Google Scholar
    • Export Citation
  • Maxfield FR & van Meer G 2010 Cholesterol, the central lipid of mammalian cells. Current Opinion in Cell Biology 22 422429. doi:10.1016/j.ceb.2010.05.004.

    • Search Google Scholar
    • Export Citation
  • Mencarelli C, Losen M, Hammels C, De Vry J, Hesselink MK, Steinbusch HW, De Baets MH & Martinez-Martinez P 2010 The ceramide transporter and the Goodpasture antigen binding protein: one protein – one function? Journal of Neurochemistry 113 13691386. doi:10.1111/j.1471-4159.2010.06673.x.

    • Search Google Scholar
    • Export Citation
  • Mesmin B & Maxfield FR 2009 Intracellular sterol dynamics. Biochimica et Biophysica Acta 1791 636645. doi:10.1016/j.bbalip.2009.03.002.

  • Mesmin B, Pipalia NH, Lund FW, Ramlall TF, Sokolov A, Eliezer D & Maxfield FR 2011 STARD4 abundance regulates sterol transport and sensing. Molecular Biology of the Cell (In press) doi:10.1091/mbc.E11-04-0372.

    • Search Google Scholar
    • Export Citation
  • Miller WL 2007 StAR search – what we know about how the steroidogenic acute regulatory protein mediates mitochondrial cholesterol import. Molecular Endocrinology 21 589601. doi:10.1210/me.2006-0303.

    • Search Google Scholar
    • Export Citation
  • Montero J, Morales A, Llacuna L, Lluis JM, Terrones O, Basanez G, Antonsson B, Prieto J, Garcia-Ruiz C & Colell A 2008 Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Research 68 52465256. doi:10.1158/0008-5472.CAN-07-6161.

    • Search Google Scholar
    • Export Citation
  • Montero J, Mari M, Colell A, Morales A, Basanez G, Garcia-Ruiz C & Fernandez-Checa JC 2010 Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death. Biochimica et Biophysica Acta 1797 12171224. doi:10.1016/j.bbabio.2010.02.010.

    • Search Google Scholar
    • Export Citation
  • Moog-Lutz C, Tomasetto C, Regnier CH, Wendling C, Lutz Y, Muller D, Chenard MP, Basset P & Rio MC 1997 MLN64 exhibits homology with the steroidogenic acute regulatory protein (STAR) and is over-expressed in human breast carcinomas. International Journal of Cancer 71 183191. doi:10.1002/(SICI)1097-0215(19970410)71:2<183::AID-IJC10>3.0.CO;2-J.

    • Search Google Scholar
    • Export Citation
  • Murcia M, Faraldo-Gomez JD, Maxfield FR & Roux B 2006 Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol. Journal of Lipid Research 47 26142630. doi:10.1194/jlr.M600232-JLR200.

    • Search Google Scholar
    • Export Citation
  • Murphy NC, Biankin AV, Millar EK, McNeil CM, O'Toole SA, Segara D, Crea P, Olayioye MA, Lee CS & Fox SB 2009 Loss of STARD10 expression identifies a group of poor prognosis breast cancers independent of HER2/Neu and triple negative status. International Journal of Cancer 126 14451453. doi:10.1002/ijc.24826.

    • Search Google Scholar
    • Export Citation
  • Ng DC, Chan SF, Kok KH, Yam JW, Ching YP, Ng IO & Jin DY 2006 Mitochondrial targeting of growth suppressor protein DLC2 through the START domain. FEBS Letters 580 191198. doi:10.1016/j.febslet.2005.11.073.

    • Search Google Scholar
    • Export Citation
  • Ngo MH, Colbourne TR & Ridgway ND 2010 Functional implications of sterol transport by the oxysterol-binding protein gene family. Biochemical Journal 429 1324. doi:10.1042/BJ20100263.

    • Search Google Scholar
    • Export Citation
  • Ning Y, Bai Q, Lu H, Li X, Pandak WM, Zhao F, Chen S, Ren S & Yin L 2009a Overexpression of mitochondrial cholesterol delivery protein, StAR, decreases intracellular lipids and inflammatory factors secretion in macrophages. Atherosclerosis 204 114120. doi:10.1016/j.atherosclerosis.2008.09.006.

    • Search Google Scholar
    • Export Citation
  • Ning Y, Xu L, Ren S, Pandak WM, Chen S & Yin L 2009b StAR overexpression decreases serum and tissue lipids in apolipoprotein E-deficient mice. Lipids 44 511519. doi:10.1007/s11745-009-3299-1.

    • Search Google Scholar
    • Export Citation
  • Olayioye MA, Hoffmann P, Pomorski T, Armes J, Simpson RJ, Kemp BE, Lindeman GJ & Visvader JE 2004 The phosphoprotein StarD10 is overexpressed in breast cancer and cooperates with ErbB receptors in cellular transformation. Cancer Research 64 35383544. doi:10.1158/0008-5472.CAN-03-3731.

    • Search Google Scholar
    • Export Citation
  • Olayioye MA, Vehring S, Muller P, Herrmann A, Schiller J, Thiele C, Lindeman GJ, Visvader JE & Pomorski T 2005 StarD10, a START domain protein overexpressed in breast cancer, functions as a phospholipid transfer protein. Journal of Biological Chemistry 280 2743627442. doi:10.1074/jbc.M413330200.

    • Search Google Scholar
    • Export Citation
  • Olayioye MA, Buchholz M, Schmid S, Schoffler P, Hoffmann P & Pomorski T 2007 Phosphorylation of StarD10 on serine 284 by casein kinase II modulates its lipid transfer activity. Journal of Biological Chemistry 282 2249222498. doi:10.1074/jbc.M701990200.

    • Search Google Scholar
    • Export Citation
  • Pandak WM, Ren S, Marques D, Hall E, Redford K, Mallonee D, Bohdan P, Heuman D, Gil G & Hylemon P 2002 Transport of cholesterol into mitochondria is rate-limiting for bile acid synthesis via the alternative pathway in primary rat hepatocytes. Journal of Biological Chemistry 277 4815848164. doi:10.1074/jbc.M205244200.

    • Search Google Scholar
    • Export Citation
  • Papadopoulos V, Liu J & Culty M 2007 Is there a mitochondrial signaling complex facilitating cholesterol import? Molecular and Cellular Endocrinology 265–266 5964. doi:10.1016/j.mce.2006.12.004.

    • Search Google Scholar
    • Export Citation
  • Pon LA, Epstein LF & Orme-Johnson NR 1986a Acute cAMP stimulation in Leydig cells: rapid accumulation of a protein similar to that detected in adrenal cortex and corpus luteum. Endocrine Research 12 429446. doi:10.3109/07435808609035449.

    • Search Google Scholar
    • Export Citation
  • Pon LA, Hartigan JA & Orme-Johnson NR 1986b Acute ACTH regulation of adrenal corticosteroid biosynthesis. Rapid accumulation of a phosphoprotein. Journal of Biological Chemistry 261 1330913316.

    • Search Google Scholar
    • Export Citation
  • Ponting CP 1995 SAM: a novel motif in yeast sterile and Drosophila polyhomeotic proteins. Protein Science 4 19281930. doi:10.1002/pro.5560040927.

    • Search Google Scholar
    • Export Citation
  • Ponting CP & Aravind L 1999 START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. Trends in Biochemical Sciences 24 130132. doi:10.1016/S0968-0004(99)01362-6.

    • Search Google Scholar
    • Export Citation
  • Prinz WA 2007 Non-vesicular sterol transport in cells. Progress in Lipid Research 46 297314. doi:10.1016/j.plipres.2007.06.002.

  • Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ & Sanyal AJ 2007 A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46 10811090. doi:10.1002/hep.21763.

    • Search Google Scholar
    • Export Citation
  • Qin C, Nagao T, Grosheva I, Maxfield FR & Pierini LM 2006 Elevated plasma membrane cholesterol content alters macrophage signaling and function. Arteriosclerosis, Thrombosis, and Vascular Biology 26 372378. doi:10.1161/01.ATV.0000197848.67999.e1.

    • Search Google Scholar
    • Export Citation
  • Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS & Goldstein JL 2007 Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig. PNAS 104 65116518. doi:10.1073/pnas.0700899104.

    • Search Google Scholar
    • Export Citation
  • Rajendran L & Simons K 2005 Lipid rafts and membrane dynamics. Journal of Cell Science 118 10991102. doi:10.1242/jcs.01681.

  • Ren S, Hylemon P, Marques D, Hall E, Redford K, Gil G & Pandak WM 2004a Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis. Journal of Lipid Research 45 21232131. doi:10.1194/jlr.M400233-JLR200.

    • Search Google Scholar
    • Export Citation
  • Ren S, Hylemon PB, Marques D, Gurley E, Bodhan P, Hall E, Redford K, Gil G & Pandak WM 2004b Overexpression of cholesterol transporter StAR increases in vivo rates of bile acid synthesis in the rat and mouse. Hepatology 40 910917. doi:10.1002/hep.1840400421.

    • Search Google Scholar
    • Export Citation
  • Riedl SJ & Salvesen GS 2007 The apoptosome: signalling platform of cell death. Nature Review. Molecular and Cellular Biology 8 405413. doi:10.1038/nrm2153.

    • Search Google Scholar
    • Export Citation
  • Riegelhaupt JJ, Waase MP, Garbarino J, Cruz DE & Breslow JL 2010 Targeted disruption of steroidogenic acute regulatory protein D4 leads to modest weight reduction and minor alterations in lipid metabolism. Journal of Lipid Research 51 11341143. doi:10.1194/jlr.M003095.

    • Search Google Scholar
    • Export Citation
  • Roderick SL, Chan WW, Agate DS, Olsen LR, Vetting MW, Rajashankar KR & Cohen DE 2002 Structure of human phosphatidylcholine transfer protein in complex with its ligand. Nature Structural Biology 9 507511. doi:10.1038/nsb812.

    • Search Google Scholar
    • Export Citation
  • Rodriguez-Agudo D, Ren S, Hylemon PB, Redford K, Natarajan R, Del Castillo A, Gil G & Pandak WM 2005 Human StarD5, a cytosolic StAR-related lipid binding protein. Journal of Lipid Research 46 16151623. doi:10.1194/jlr.M400501-JLR200.

    • Search Google Scholar
    • Export Citation
  • Rodriguez-Agudo D, Ren S, Hylemon PB, Montanez R, Redford K, Natarajan R, Medina MA, Gil G & Pandak WM 2006 Localization of StarD5 cholesterol binding protein. Journal of Lipid Research 47 11681175. doi:10.1194/jlr.M500447-JLR200.

    • Search Google Scholar
    • Export Citation
  • Rodriguez-Agudo D, Ren S, Wong E, Marques D, Redford K, Gil G, Hylemon P & Pandak WM 2008 Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation. Journal of Lipid Research 49 14091419. doi:10.1194/jlr.M700537-JLR200.

    • Search Google Scholar
    • Export Citation
  • Rodriguez-Agudo D, Calderon-Dominguez M, Ren S, Marques D, Redford K, Medina-Torres MA, Hylemon P, Gil G & Pandak WM 2011 Subcellular localization and regulation of StarD4 protein in macrophages and fibroblasts. Biochimica et Biophysica Acta 1811 597606. doi:10.1016/j.bbalip.2011.06.028.

    • Search Google Scholar
    • Export Citation
  • Romanowski MJ, Soccio RE, Breslow JL & Burley SK 2002 Crystal structure of the Mus musculus cholesterol-regulated START protein 4 (StarD4) containing a StAR-related lipid transfer domain. PNAS 99 69496954. doi:10.1073/pnas.052140699.

    • Search Google Scholar
    • Export Citation
  • Rone MB, Fan J & Papadopoulos V 2009 Cholesterol transport in steroid biosynthesis: role of protein–protein interactions and implications in disease states. Biochimica et Biophysica Acta 1791 646658. doi:10.1016/j.bbalip.2009.03.001.

    • Search Google Scholar
    • Export Citation
  • Rosenbaum AI & Maxfield FR 2011 Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. Journal of Neurochemistry 116 789795. doi:10.1111/j.1471-4159.2010.06976.x.

    • Search Google Scholar
    • Export Citation
  • Russell DW 2003 The enzymes, regulation, and genetics of bile acid synthesis. Annual Review of Biochemistry 72 137174. doi:10.1146/annurev.biochem.72.121801.161712.

    • Search Google Scholar
    • Export Citation
  • Sakai JA & Rawson RB 2001 The sterol regulatory element-binding protein pathway: control of lipid homeostasis through regulated intracellular transport. Current Opinion in Lipidology 12 261266. doi:10.1097/00041433-200106000-00004.

    • Search Google Scholar
    • Export Citation
  • Sasaki G, Ishii T, Jeyasuria P, Jo Y, Bahat A, Orly J, Hasegawa T & Parker KL 2008 Complex role of the mitochondrial targeting signal in the function of steroidogenic acute regulatory protein revealed by bacterial artificial chromosome transgenesis in vivo. Molecular Endocrinology 22 951964. doi:10.1210/me.2007-0493.

    • Search Google Scholar
    • Export Citation
  • Scapa EF, Pocai A, Wu MK, Gutierrez-Juarez R, Glenz L, Kanno K, Li H, Biddinger S, Jelicks LA & Rossetti L 2008 Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2. FASEB Journal 22 25792590. doi:10.1096/fj.07-105395.

    • Search Google Scholar
    • Export Citation
  • Scholz RP, Regner J, Theil A, Erlmann P, Holeiter G, Jahne R, Schmid S, Hausser A & Olayioye MA 2009 DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling. Journal of Cell Science 122 92102. doi:10.1242/jcs.036251.

    • Search Google Scholar
    • Export Citation
  • Scholz R-P, Gustafsson JOR, Hoffmann P, Jaiswal M, Ahmadian MR, Eisler SA, Erlmann P, Schmid S, Hausser A & Olayioye MA 2011 The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation. Experimental Cell Research 317 496503. doi:10.1016/j.yexcr.2010.11.003.

    • Search Google Scholar
    • Export Citation
  • Schrick K, Nguyen D, Karlowski WM & Mayer KF 2004 START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors. Genome Biology 5 R41 doi:10.1186/gb-2004-5-6-r41.

    • Search Google Scholar
    • Export Citation
  • Shishova EY, Stoll JM, Ersoy BA, Shrestha S, Scapa EF, Li Y, Niepel MW, Su Y, Jelicks LA & Stahl GL 2011 Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. Hepatology 54 664674. doi:10.1002/hep.24393.

    • Search Google Scholar
    • Export Citation
  • Siperstein MD & Fagan VM 1964 Deletion of the cholesterol-negative feedback system in liver tumors. Cancer Research 24 11081115.

  • Soccio RE & Breslow JL 2003 StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. Journal of Biological Chemistry 278 2218322186. doi:10.1074/jbc.R300003200.

    • Search Google Scholar
    • Export Citation
  • Soccio RE & Breslow JL 2004 Intracellular cholesterol transport. Arteriosclerosis, Thrombosis, and Vascular Biology 24 11501160. doi:10.1161/01.ATV.0000131264.66417.d5.

    • Search Google Scholar
    • Export Citation
  • Soccio RE, Adams RM, Romanowski MJ, Sehayek E, Burley SK & Breslow JL 2002 The cholesterol-regulated StarD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, StarD5 and StarD6. PNAS 99 69436948. doi:10.1073/pnas.052143799.

    • Search Google Scholar
    • Export Citation
  • Soccio RE, Adams RM, Maxwell KN & Breslow JL 2005 Differential gene regulation of StarD4 and StarD5 cholesterol transfer proteins: activation of StARD4 by sterol regulatory element-binding protein-2 and StARD5 by endoplasmic reticulum stress. Journal of Biological Chemistry 280 1941019418. doi:10.1074/jbc.M501778200.

    • Search Google Scholar
    • Export Citation
  • Stocco DM 2001 StAR protein and the regulation of steroid hormone biosynthesis. Annual Review of Physiology 63 193213. doi:10.1146/annurev.physiol.63.1.193.

    • Search Google Scholar
    • Export Citation
  • Stocco DM & Chen W 1991 Presence of identical mitochondrial proteins in unstimulated constitutive steroid-producing R2C rat Leydig tumor and stimulated nonconstitutive steroid-producing MA-10 mouse Leydig tumor cells. Endocrinology 128 19181926. doi:10.1210/endo-128-4-1918.

    • Search Google Scholar
    • Export Citation
  • Stocco DM & Clark BJ 1996 Regulation of the acute production of steroids in steroidogenic cells. Endocrinology Reviews 17 221244. doi:10.1210/edrv-17-3-221.

    • Search Google Scholar
    • Export Citation
  • Stocco DM & Sodeman TC 1991 The 30-kDa mitochondrial proteins induced by hormone stimulation in MA-10 mouse Leydig tumor cells are processed from larger precursors. Journal of Biological Chemistry 266 1973119738.

    • Search Google Scholar
    • Export Citation
  • Strauss JF III, Kishida T, Christenson LK, Fujimoto T & Hiroi H 2003 START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Molecular and Cellular Endocrinology 202 5965. doi:10.1016/S0303-7207(03)00063-7.

    • Search Google Scholar
    • Export Citation
  • Suematsu N & Isohashi F 2006 Molecular cloning and functional expression of human cytosolic acetyl-CoA hydrolase. Acta Biochimica Polonica 53 553561.

    • Search Google Scholar
    • Export Citation
  • Suematsu N, Okamoto K, Shibata K, Nakanishi Y & Isohashi F 2001 Molecular cloning and functional expression of rat liver cytosolic acetyl-CoA hydrolase. European Journal of Biochemistry 268 27002709. doi:10.1046/j.1432-1327.2001.02162.x.

    • Search Google Scholar
    • Export Citation
  • Suematsu N, Okamoto K & Isohashi F 2002 Mouse cytosolic acetyl-CoA hydrolase, a novel candidate for a key enzyme involved in fat metabolism: cDNA cloning, sequencing and functional expression. Acta Biochimica Polonica 49 937945.

    • Search Google Scholar
    • Export Citation
  • Sugawara T, Lin D, Holt JA, Martin KO, Javitt NB, Miller WL & Strauss JF III 1995 Structure of the human steroidogenic acute regulatory protein (StAR) gene: StAR stimulates mitochondrial cholesterol 27-hydroxylase activity. Biochemistry 34 1250612512. doi:10.1021/bi00039a004.

    • Search Google Scholar
    • Export Citation
  • Sun LP, Seemann J, Goldstein JL & Brown MS 2007 Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. PNAS 104 65196526. doi:10.1073/pnas.0700907104.

    • Search Google Scholar
    • Export Citation
  • Taylor JM, Borthwick F, Bartholomew C & Graham A 2010 Overexpression of steroidogenic acute regulatory protein increases macrophage cholesterol efflux to apolipoprotein AI. Cardiovascular Research 86 526534. doi:10.1093/cvr/cvq015.

    • Search Google Scholar
    • Export Citation
  • Thorsell AG, Lee WH, Persson C, Siponen MI, Nilsson M, Busam RD, Kotenyova T, Schuler H & Lehtio L 2011 Comparative structural analysis of lipid binding START domains. PLoS ONE 6 e19521 doi:10.1371/journal.pone.0019521.

    • Search Google Scholar
    • Export Citation
  • Tomasetto C, Regnier C, Moog-Lutz C, Mattei MG, Chenard MP, Lidereau R, Basset P & Rio MC 1995 Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11–q21.3 region of chromosome 17. Genomics 28 367376. doi:10.1006/geno.1995.1163.

    • Search Google Scholar
    • Export Citation
  • Tsai YC & Weissman AM 2010 The unfolded protein response, degradation from endoplasmic reticulum and cancer. Genes and Cancer 1 764778. doi:10.1177/1947601910383011.

    • Search Google Scholar
    • Export Citation
  • Tsujishita Y & Hurley JH 2000 Structure and lipid transport mechanism of a StAR-related domain. Nature Structural Biology 7 408414. doi:10.1038/75192.

    • Search Google Scholar
    • Export Citation
  • Van Rooyen DM & Farrell GC 2011 SREBP-2: a link between insulin resistance, hepatic cholesterol, and inflammation in NASH. Journal of Gastroenterology and Hepatology 26 789792. doi:10.1111/j.1440-1746.2011.06704.x.

    • Search Google Scholar
    • Export Citation
  • Van Rooyen DM, Larter CZ, Haigh WG, Yeh MM, Ioannou G, Kuver R, Lee SP, Teoh NC & Farrell GC 2011 Hepatic free cholesterol accumulates in obese, diabetic mice and causes non-alcoholic steatohepatitis. Gastroenterology 141 13931403. doi:10.1053/j.gastro.2011.06.040.

    • Search Google Scholar
    • Export Citation
  • Wang ML, Motamed M, Infante RE, Abi-Mosleh L, Kwon HJ, Brown MS & Goldstein JL 2010 Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. Cell Metabolism 12 166173. doi:10.1016/j.cmet.2010.05.016.

    • Search Google Scholar
    • Export Citation
  • Wollam J & Antebi A 2011 Sterol regulation of metabolism, homeostasis, and development. Annual Review of Biochemistry 80 885916. doi:10.1146/annurev-biochem-081308-165917.

    • Search Google Scholar
    • Export Citation
  • Yamada S, Yamaguchi T, Hosoda A, Iwawaki T & Kohno K 2006 Regulation of human STARD4 gene expression under endoplasmic reticulum stress. Biochemical and Biophysical Research Communications 343 10791085. doi:10.1016/j.bbrc.2006.03.051.

    • Search Google Scholar
    • Export Citation
  • Yamaga M, Sekimata M, Fujii M, Kawai K, Kamata H, Hirata H, Homma Y & Yagisawa H 2004 A PLCdelta1-binding protein, p122/RhoGAP, is localized in caveolin-enriched membrane domains and regulates caveolin internalization. Genes to Cells 9 2537. doi:10.1111/j.1356-9597.2004.00698.x.

    • Search Google Scholar
    • Export Citation
  • Yau TO, Leung TH, Lam S, Cheung OF, Tung EK, Khong PL, Lam A, Chung S & Ng IO 2009 Deleted in liver cancer 2 (DLC2) was dispensable for development and its deficiency did not aggravate hepatocarcinogenesis. PLoS ONE 4 e6566 doi:10.1371/journal.pone.0006566.

    • Search Google Scholar
    • Export Citation
  • Yaworsky DC, Baker BY, Bose HS, Best KB, Jensen LB, Bell JD, Baldwin MA & Miller WL 2005 pH-dependent interactions of the carboxyl-terminal helix of steroidogenic acute regulatory protein with synthetic membranes. Journal of Biological Chemistry 280 20452054. doi:10.1074/jbc.M410937200.

    • Search Google Scholar
    • Export Citation
  • Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL & Brown MS 1993 SREBP-1, a basic-helix–loop–helix–leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75 187197. doi:10.1016/S0092-8674(05)80095-9.

    • Search Google Scholar
    • Export Citation
  • Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS & Popescu NC 1998 Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Research 58 21962199.

    • Search Google Scholar
    • Export Citation

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    Model for non-vesicular cholesterol trafficking by the START domain proteins. The cholesterol-binding START proteins are shown at subcellular locations identified by immunohistochemistry (Alpy et al. 2001, Rodriguez-Agudo et al. 2005, Chen et al. 2009). STARD4 stimulates ACAT activity and increases CE synthesis and, therefore, is depicted in close proximity to ACAT at the ER membrane (Rodriguez-Agudo et al. 2011). STARD5 does not stimulate ACAT activity and is shown at different ER sites than STARD4 to indicate potential different functions. The SREBP2 pathway is cartooned to show activation of SREBP2 target genes HMGR, LDLR, and STARD4. The ER to PM and PM to ER cholesterol trafficking is shown to be mediated by a START protein. Although no data have directly demonstrated START proteins in this directional cholesterol trafficking pathway, STARD5 is presented as shuttling cholesterol from the PM to the ER as an example for a START protein in this process based on the apical membrane association renal proximal tubule cells (Chen et al. 2009). Cholesterol transport to mitochondria by STARD1 and STARD4. STARD1 binds cholesterol and facilitates its translocation into the matrix to the P450scc or CYP27A1 enzyme for steroid hormone or oxysterol synthesis respectively. Cholesterol in late endosome/lysosomes is transported to the PM and ER. STARD3/MLN64 in late endosomes is depicted as the intermediate between late endosome/lysosome cholesterol and a soluble cytoplasmic START protein, potentially STARD4 or STARD5. STARD3/MLN64 may obtain cholesterol from NPC2 or MENTHO directly or from NPC1 (see text for details). Cholesterol accumulation in the ER will promote ER stress that can induce STARD5 and STARD4 expression. The purpose for START protein induction upon ER stress is not known and future studies are required to determine whether they are protective or detrimental to the stress response. Solid arrows, vesicular transport; dashed arrows, non-vesicular transport.

  • Adams SH, Chui C, Schilbach SL, Yu XX, Goddard AD, Grimaldi JC, Lee J, Dowd P, Colman S & Lewin DA 2001 BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity. Biochemical Journal 360 135142. doi:10.1042/0264-6021:3600135.

    • Search Google Scholar
    • Export Citation
  • Alberta JA, Epstein LF, Pon LA & Orme-Johnson NR 1989 Mitochondrial localization of a phosphoprotein that rapidly accumulates in adrenal cortex cells exposed to adrenocorticotropic hormone or to cAMP. Journal of Biological Chemistry 264 23682372.

    • Search Google Scholar
    • Export Citation
  • Alirol E & Martinou JC 2006 Mitochondria and cancer: is there a morphological connection? Oncogene 25 47064716. doi:10.1038/sj.onc.1209600.

  • Alpy F & Tomasetto C 2005 Give lipids a START: the StAR-related lipid transfer (START) domain in mammals. Journal of Cell Science 118 27912801. doi:10.1242/jcs.02485.

    • Search Google Scholar
    • Export Citation
  • Alpy F & Tomasetto C 2006 MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochemical Society Transactions 34 343345. doi:10.1042/BST0340343.

    • Search Google Scholar
    • Export Citation
  • Alpy F, Stoeckel ME, Dierich A, Escola JM, Wendling C, Chenard MP, Vanier MT, Gruenberg J, Tomasetto C & Rio MC 2001 The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. Journal of Biological Chemistry 276 42614269. doi:10.1074/jbc.M006279200.

    • Search Google Scholar
    • Export Citation
  • Alpy F, Latchumanan VK, Kedinger V, Janoshazi A, Thiele C, Wendling C, Rio MC & Tomasetto C 2005 Functional characterization of the MENTAL domain. Journal of Biological Chemistry 280 1794517952. doi:10.1074/jbc.M500723200.

    • Search Google Scholar
    • Export Citation
  • Anderson RGW 2003 Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends in Cell Biology 13 534539. doi:10.1016/j.tcb.2003.08.007.

    • Search Google Scholar
    • Export Citation
  • Arakane F, Sugawara T, Nishino H, Liu Z, Holt JA, Pain D, Stocco DM, Miller WL & Strauss JF III 1996 Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action. PNAS 93 1373113736. doi:10.1073/pnas.93.24.13731.

    • Search Google Scholar
    • Export Citation
  • Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM & Strauss JF III 1997 Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. Journal of Biological Chemistry 272 3265632662. doi:10.1074/jbc.272.51.32656.

    • Search Google Scholar
    • Export Citation
  • Arakane F, Kallen CB, Watari H, Foster JA, Sepuri NB, Pain D, Stayrook SE, Lewis M, Gerton GL & Strauss JF III 1998 The mechanism of action of steroidogenic acute regulatory protein (StAR). StAR acts on the outside of mitochondria to stimulate steroidogenesis. Journal of Biological Chemistry 273 1633916345. doi:10.1074/jbc.273.26.16339.

    • Search Google Scholar
    • Export Citation
  • Artemenko IP, Zhao D, Hales DB, Hales KH & Jefcoate CR 2001 Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells. Journal of Biological Chemistry 276 4658346596. doi:10.1074/jbc.M107815200.

    • Search Google Scholar
    • Export Citation
  • Babiker A & Diczfalusy U 1998 Transport of side-chain oxidized oxysterols in the human circulation. Biochimica et Biophysica Acta 1392 333339. doi:10.1016/S0005-2760(98)00047-2.

    • Search Google Scholar
    • Export Citation
  • Bai Q, Li X, Ning Y, Zhao F & Yin L 2009 Mitochondrial cholesterol transporter, StAR, inhibits human THP-1 monocyte-derived macrophage apoptosis. Lipids 45 2936. doi:10.1007/s11745-009-3375-6.

    • Search Google Scholar
    • Export Citation
  • Baker BY, Yaworsky DC & Miller WL 2005 A pH-dependent molten globule transition is required for activity of the steroidogenic acute regulatory protein, StAR. Journal of Biological Chemistry 280 4175341760. doi:10.1074/jbc.M510241200.

    • Search Google Scholar
    • Export Citation
  • Baker BY, Epand RF, Epand RM & Miller WL 2007 Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR. Journal of Biological Chemistry 282 1022310232. doi:10.1074/jbc.M611221200.

    • Search Google Scholar
    • Export Citation
  • Barbar E, Lavigne P & Lehoux JG 2009 Validation of the mechanism of cholesterol binding by StAR using short molecular dynamics simulations. Journal of Steroid Biochemistry and Molecular Biology 113 9297. doi:10.1016/j.jsbmb.2008.11.008.

    • Search Google Scholar
    • Export Citation
  • Bjorkhem I, Diczfalusy U & Lutjohann D 1999 Removal of cholesterol from extrahepatic sources by oxidative mechanisms. Current Opinion in Lipidology 10 161165. doi:10.1097/00041433-199904000-00010.

    • Search Google Scholar
    • Export Citation
  • Borthwick F, Allen AM, Taylor JM & Graham A 2010 Overexpression of STARD3 in human monocyte/macrophages induces an anti-atherogenic lipid phenotype. Clinical Science 119 265272. doi:10.1042/CS20100266.

    • Search Google Scholar
    • Export Citation
  • Bose HS, Sugawara T, Strauss JF III & Miller WL 1996 The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. New England Journal of Medicine 335 18701878. doi:10.1056/NEJM199612193352503.

    • Search Google Scholar
    • Export Citation
  • Bose HS, Whittal RM, Baldwin MA & Miller WL 1999 The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. PNAS 96 72507255. doi:10.1073/pnas.96.13.7250.

    • Search Google Scholar
    • Export Citation
  • Bose H, Lingappa VR & Miller WL 2002 Rapid regulation of steroidogenesis by mitochondrial protein import. Nature 417 8791. doi:10.1038/417087a.

  • Bose HS, Whittal RM, Ran Y, Bose M, Baker BY & Miller WL 2008a StAR-like activity and molten globule behavior of StARD6, a male germ-line protein. Biochemistry 47 22772288. doi:10.1021/bi701966a.

    • Search Google Scholar
    • Export Citation
  • Bose M, Whittal RM, Miller WL & Bose HS 2008b Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein. Journal of Biological Chemistry 283 88378845. doi:10.1074/jbc.M709221200.

    • Search Google Scholar
    • Export Citation
  • Brown MS & Goldstein JL 2009 Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL. Journal of Lipid Research 50 (Suppl) S15S27. doi:10.1194/jlr.R800054-JLR200.

    • Search Google Scholar
    • Export Citation
  • Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J & Garcia-Ruiz C 2009 Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. Journal of Hepatology 50 789796. doi:10.1016/j.jhep.2008.12.016.

    • Search Google Scholar
    • Export Citation
  • Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ & Parker KL 1997 Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. PNAS 94 1154011545. doi:10.1073/pnas.94.21.11540.

    • Search Google Scholar
    • Export Citation
  • Chang IY, Kim JK, Lee SM, Kim JN, Soh J, Kim JW & Yoon SP 2009 The changed immunoreactivity of StarD6 after pilocarpine-induced epilepsy. Neuroreport 20 963967. doi:10.1097/WNR.0b013e32832ca264.

    • Search Google Scholar
    • Export Citation
  • Charman M, Kennedy BE, Osborne N & Karten B 2009 MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. Journal of Lipid Research 51 10231034. doi:10.1194/jlr.M002345.

    • Search Google Scholar
    • Export Citation
  • Chen Y-C, Meier RK, Zheng S, Khundmiri SJ, Tseng