Abstract
Obesity and ectopic fat accumulation in non-adipose tissues are major contributors to heart failure (HF) and cardiovascular disease (CVD). Adipocytes act as endocrine organs by releasing a large number of bioactive molecules into the bloodstream, which participate in a communication network between white adipose tissue and other organs, including the heart. Among these molecules, fatty acid-binding protein 4 (FABP4) has recently been shown to increase cardiometabolic risk. Both clinical and experimental evidence have identified FABP4 as a relevant player in atherosclerosis and coronary artery disease, and it has been directly related to cardiac alterations such as left ventricular hypertrophy (LVH) and both systolic and diastolic cardiac dysfunction. The available interventional studies preclude the establishment of a direct causal role of this molecule in CVD and HF and propose FABP4 as a biomarker rather than as an aetiological factor. However, several experimental reports have suggested that FABP4 may act as a direct contributor to cardiac metabolism and physiopathology, and the pharmacological targeting of FABP4 may restore some of the metabolic alterations that are conducive to CVD and HF. Here, we review the current knowledge regarding FABP4 in the context of HF and CVD as well as the molecular basis by which this protein participates in the regulation of cardiac function.
Introduction
Heart failure (HF) is one of the most important health problems around the world (for a review, see Hunt et al. 2009). The prevalence of HF is especially ominous in developed societies. Between the EU and the United States, there are more than 20 million people afflicted with this pathology (Mosterd & Hoes 2007, Mozaffarian et al. 2015). It is estimated that HF is currently the leading cause of hospitalisation in people over the age of 65 years (Forman et al. 2009), and approximately 108 billion dollars are spent each year on health costs associated with this pathology (Stewart et al. 2002, Neumann et al. 2009, Cook et al. 2014). Despite advances in the treatment of HF and the amount of money invested to combating this pathology, the number of deaths as a consequence of HF is steadily increasing. It is predicted that up to 30% of HF patients will die within 1 year following hospitalisation, and half will die within 5 years of their initial diagnosis (Loehr et al. 2008, Writing Group et al. 2010).
Increasing evidence has highlighted the role of metabolic diseases as important risk factors for HF. In particular, obesity has been proposed as one of the main contributors to the onset and progression of HF (Lavie et al. 2009). Despite the obesity-related comorbidities that may explain part of this association, a direct relationship between the risk of HF and adipokines has also been proposed (Baldasseroni et al. 2012, Djousse et al. 2013, Liu et al. 2013). Among these adipokines, fatty acid-binding protein 4 (FABP4) has recently been linked to cardiovascular and metabolic diseases. Additionally, FABP4 is highly expressed in macrophages, contributing to the development of atherosclerosis and cardiovascular disease (CVD). Here, we will review the current knowledge of FABP4 in HF and CVD as well as the molecular basis by which this protein participates in the regulation of cardiac function.
Obesity as a risk factor for heart failure
Among the risk factors for HF, we identified the so-called metabolic syndrome, which encompasses multiple metabolic disorders, including high blood pressure, dyslipidaemia, insulin resistance and obesity (Wang et al. 2010). Specifically, both overweight and obesity have been closely related to HF and other CVDs (Lavie et al. 2009). Recently, several studies have demonstrated a positive correlation between obesity/overweight and the risk of developing HF. A 5–7% increase in the incidence of HF per unit of increased body mass index (BMI) (Go et al. 2014) was found in a seminal study from the Framingham Heart Study (Kenchaiah et al. 2009). Interestingly, a graded increase in the risk of HF was found across all BMI categories. Similar data were obtained from a Finnish study, showing a greater risk of HF in overweight and obese subjects than that in normal-weight participants (Hu et al. 2010). However, while some authors attribute these correlations to the downstream development of metabolic risk factors such as inflammation, insulin resistance or type 2 diabetes mellitus (Ingelsson et al. 2005, Bahrami et al. 2008, Voulgari et al. 2011), the data from other studies report that obesity directly correlates with the risk of HF, independent of other metabolic risk factors (Morkedal et al. 2014). Paradoxically, once HF has been established, obesity confers survival benefits (Oreopoulos et al. 2008, Shah et al. 2014). Despite the exploration of the role of confounding factors, the underlying mechanism that explains this finding remains unclear. Interestingly, this paradox is not evident in obese patients with diabetes (Zamora et al. 2016).
Some pathological conditions that are present in obese patients may be involved in the elevated risk of HF. Both visceral obesity and ectopic fat accumulation in non-adipose tissues, including the heart, have been related to cardiac structure abnormalities and increased cardiometabolic risk (Britton & Fox 2011). Cardiac steatosis has been found in subjects with dilated cardiomyopathy (Graner et al. 2014), and pericardial fat accumulation is independently correlated with left ventricular (LV) mass and is inversely correlated with LV mid-wall stress abnormalities in morbidly obese patients (Graner et al. 2014). As an endocrine organ, adipose tissue produces and secretes a wide range of bioactive factors known as adipokines, which take part in the network of communication between adipose tissue and peripheral organs, including the heart (Kershaw & Flier 2004). The most studied adipokines are adiponectin, leptin, resistin, plasminogen activator inhibitor-1 (PAI-1) and tumour necrosis factor α (TNFα); however, increasing evidence has proposed fatty acid-binding protein 4 (FABP4) as a new emerging adipokine involved in the development of metabolic disease and CVD. Apart from adipocytes, FABP4 is also highly expressed in macrophages and dendritic cells (Makowski et al. 2001, Rolph et al. 2006), further contributing to inflammation-related alterations, such as metabolic syndrome and CVD.
Fatty acid-binding protein 4
FABP4, also known as adipocyte FABP (A-FABP) or adipocyte P2 (aP2), belongs to a family of intracellular lipid chaperones that is expressed in active lipid metabolic tissues. Similar to other members of the FABP family, FABP4 is able to reversibly bind to hydrophobic ligands such as saturated and unsaturated long-chain fatty acids (FA), eicosanoids and other lipids (Coe & Bernlohr 1998, Zimmerman & Veerkamp 2002), thus taking part in the regulation of lipid trafficking and responses at the cellular level (Furuhashi & Hotamisligil 2008, Furuhashi et al. 2011). Specifically, FABPs have been proposed to actively facilitate the transport of FA to specific organelles in the cell, including mitochondria, peroxisomes, the nucleus and the endoplasmic reticulum. Therefore, FABPs take part in lipid oxidation, lipid-mediated transcriptional regulation and the signalling, trafficking and synthesis of membranes (Furuhashi & Hotamisligil 2008). In addition, FABPs also take part in the regulation of the enzymatic activity and storage of lipid droplets in the cytoplasm (Furuhashi & Hotamisligil 2008), the conversion of FA to eicosanoids and the stabilisation of leukotrienes (Ek et al. 1997, Zimmer et al. 2004). Apart from FABP4, the FABP family is composed of eight other isoforms in mammals based on tissue distribution, including the liver (FABP1), intestines (FABP2), heart (FABP3), epidermis (FABP5), ileum (FABP6), brain (FABP7), myelin (FABP8) and testis (FABP9). Despite the wide range of sequence identity between the different members of the FABP family (15–70%) (Chmurzynska 2006), all members share similar three-dimensional structures, including two orthogonal 5-stranded β-sheets and a 10-stranded anti-parallel β-barrel structure (Chmurzynska 2006, Marr et al. 2006, Furuhashi & Hotamisligil 2008) (Fig. 1).
Specifically, the human FABP4 gene encodes a polypeptide of 132 amino acids in length with a molecular mass of 14.6 kDa (GenBank accession number NM_024406). FABP4 expression is strongly induced during adipocyte differentiation (Bernlohr et al. 1985a), which has led to proposals of this molecule as an adipocyte differentiation marker (Bernlohr et al. 1985b, Smith et al. 1988, Yang et al. 1989). Similar to adipocytes, FABP4 expression is also induced during differentiation from monocytes to macrophages, and its expression in these cells is regulated by a wide range of proinflammatory stimuli (Pelton et al. 1999, Fu et al. 2000, Makowski et al. 2001, Fu et al. 2002, Kazemi et al. 2005, Wang et al. 2011). In macrophages, FABP4 increases the accumulation of cholesterol ester and induces foam cell formation as well as inflammatory responses through the activation of the IKK-NF-κB and JNK-AP-1 pathways (Makowski et al. 2005, Hui et al. 2010). FABP4 expression is controlled at the transcriptional level by CEBP (CCAAT/enhancer-binding protein) (Christy et al. 1989) and PPARγ (peroxisome proliferator-activated receptor γ) (Kletzien et al. 1992, Cabre et al. 2007). Additionally, cAMP (cyclic adenosine monophosphate) further controls FABP4 expression by relieving a negative regulatory element in the FABP4 promoter (Yang et al. 1989). As mentioned previously, FABP4 acts as a lipid-binding chaperone for long-chain non-esterified fatty acids (NEFA) (Coe & Bernlohr 1998), which are transported via the interior water-filled binding cavity formed by the β-barrel (LaLonde et al. 1994) (Fig. 1). In addition, FABP4 enhances the hydrolytic activity of hormone-sensitive lipase (HSL) by a molecular mechanism involving specific protein–protein interactions (Shen et al. 2001). Furthermore, FABP4 regulates PPARγ activity by taking part in delivering specific PPARγ agonists, including thiazolidinedione and linoleic acid, from the cytosol to the nucleus (Adida & Spener 2006, Gillilan et al. 2007). Interestingly, the FABP4 nuclear localisation signal is only found in the three-dimensional structure of the protein when bound to PPARγ agonists (Ayers et al. 2007, Gillilan et al. 2007); meanwhile, the binding of other FABP4 ligands that are not PPARγ activators, including oleate or stearate, does not result in a stable nuclear localisation signal (Gillilan et al. 2007).
Altogether, FABP4 is involved in the regulation of proteins that control both lipid metabolism and insulin sensitivity. Apart from its well-known role as a lipid chaperone in adipocytes, FABP4 has been detected in the bloodstream and is independently and strongly correlated with adiposity (Xu et al. 2006, Ishimura et al. 2013). Despite its lack of an N-terminal secretory signal sequence (Furuhashi & Hotamisligil 2008), FABP4 has been reported to be released from adipocytes through additional mechanisms (Coe et al. 1999, Scheja et al. 1999, Shen et al. 1999, Mita et al. 2015) and acts as an adipokine in several organs, including the heart (Fig. 2).
FABP4 as a cardiometabolic predictor for CVD
Apart from its well-known role as an adiposity biomarker (Xu et al. 2006, Ishimura et al. 2013), FABP4 has been associated with the following distinct components of metabolic syndrome based on a Third-Generation Framingham Heart Study cohort: BMI, triglycerides, total cholesterol, diastolic blood pressure, reduced HDL levels and impaired glomerular filtration rate (eGFR) (Kaess et al. 2012). Additionally, despite the lack of an association between FABP4 and prevalent diabetes (probably because of the low prevalence of diabetes in the studied cohort), this FA transporter was positively associated with insulin resistance and low-grade inflammation, which is consistent with the multifactorial pathogenesis of metabolic dysregulation. In addition, prospective studies have shown that FABP4 can predict the development of metabolic syndrome and type 2 diabetes (Tso et al. 2007, Xu et al. 2007). Since metabolic syndrome and insulin resistance are closely linked with CVD, a strong association between circulating FABP4 levels and this pathology has also been proposed (Yeung et al. 2007, Miyoshi et al. 2010, Xu et al. 2010, Bao et al. 2011, von Eynatten et al. 2012, Fuseya et al. 2014) (Fig. 2). Recently, FABP4 plasma levels have been associated with elevated CVD mortality in men with type 2 diabetes mellitus (Liu et al. 2016). Decreased FABP4 expression as a consequence of a genetic variant of the FABP4 promoter (T-87C) results in reduced serum triglycerides and a lower risk of CVD (Tuncman et al. 2006). In addition, FABP4 deficiency reduces aortic atherosclerotic lesions and increases the survival rate of apolipoprotein-E (ApoE)-deficient mice fed with a high-fat atherogenic diet (Makowski et al. 2001, Boord et al. 2004). The impact of FABP4 on atherosclerosis is mainly due to the role of this molecule in macrophages rather than that in adipocytes, as demonstrated by studies involving bone marrow transplantation (Makowski et al. 2001). Additionally, FABP4 from dendritic cells may further impact atherosclerosis, since it regulates inflammation and T-cell priming (Rolph et al. 2006). Moreover, the pharmacological inhibition of FABP4 also significantly protected against atherosclerotic plaque formation in the ApoE-deficient animal model of atherosclerosis, suggesting that the pharmacological inhibition of FABP4 might have beneficial effects against CVD (Furuhashi et al. 2007). In humans, FABP4 has been related to subclinical coronary atherosclerosis in type 2 diabetes mellitus subjects (Bagheri et al. 2010), and circulating FABP4 levels are also associated with increased carotid intima-media thickness, ischaemic stroke, coronary atherosclerotic burden and the number of stenotic coronary arteries (Yeung et al. 2007, Rhee et al. 2009, Miyoshi et al. 2010, Xu et al. 2010, Bao et al. 2011, Doi et al. 2011, Holm et al. 2011, Tso et al. 2011, Huang et al. 2013). Recently, FABP4 has been proposed as a prognostic biomarker in patients with acute coronary syndrome (Reiser et al. 2015). In addition, FABP4 is an important predictor of cardiovascular outcomes in patients with either coronary heart disease or acute ischaemic stroke (Holm et al. 2011, von Eynatten et al. 2012). Along with its potential role as a biomarker, a 12-year prospective study performed in a cohort without previous CVD revealed that FABP4 is a potential independent risk factor that predisposes individuals to CVD, showing the predictive value of FABP4 over the predictions based on traditional risk factors (Chow et al. 2013). FABP4 levels in atherosclerotic plaques have been further associated with an unstable plaque phenotype, which predicts the occurrence of an adverse cardiovascular event (Peeters et al. 2011, Lee et al. 2013). Specifically, unstable carotid plaques have been related to increased FABP4 expression in macrophages among samples from human endarterectomy (Agardh et al. 2011). Therefore, these findings support the role of FABP4 as a potential mediator of obesity/inflammation-related CVD. However, these studies precluded the establishment of a direct causal relationship between serum FABP4 and atherosclerosis.
FABP4, cardiac dysfunction and HF
FABP4 has been directly related to cardiac alterations (Fuseya et al. 2014) (Fig. 2). Specifically, FABP4 levels are associated with LVH as well as systolic and diastolic cardiac dysfunction (Balci et al. 2012, Engeli et al. 2013, Huang et al. 2013, Liu et al. 2013, Baessler et al. 2014), even in an apparently healthy population (Fuseya et al. 2014). A positive correlation between FABP4 and both LV dysfunction and myocardial perfusion abnormalities was found in patients with coronary artery disease (Huang et al. 2013). In addition, Engeli and coworkers found a modest but significant independent correlation between FABP4 serum concentrations and the LV mass in overweight and obese women (Engeli et al. 2013). Interestingly, longitudinal systolic and diastolic function was reduced in subjects with high serum FABP4 concentrations. The correlation between elevated serum FABP4 and the deterioration of LV function had previously been reported in non-obese patients who were hospitalised for acutely decompensated HF (Liu et al. 2013). However, others have failed to show an association between FABP4 and present (Balci et al. 2012) or future (Djousse et al. 2013) systolic dysfunction in subjects without prevalent cardiac disease (Liu et al. 2013). Altogether, these studies suggest only a marginal contribution of FABP4 to the development of early systolic dysfunction in obese humans.
FABP4-related heart remodelling and cardiac dysfunction may directly contribute to the development of HF (Liu et al. 2013). Liu and coworkers provided the first clinical evidence demonstrating that serum FABP4 concentrations are significantly higher in patients with HF than those in non-HF subjects, and this association was significantly increased with the severity of HF (Liu et al. 2013). Interestingly, this association was further confirmed by others (Huang et al. 2013, Liu et al. 2013). In addition, FABP4 positively correlates with the serum levels of N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP), a well-established and powerful marker of HF risk (Tang et al. 2007), and with all echocardiograph parameters, especially LV ejection fraction (LVEF) (Liu et al. 2013). Moreover, using logistic regression analysis, the authors proposed FABP4 as an independent risk factor for HF (Liu et al. 2013). These data were reported during the review process of a study performed by members of our team that demonstrates a strong correlation between FABP4 and NT-proBNP in HF patients (Cabre et al. 2013), thus confirming the data first reported by Liu and coworkers (Liu et al. 2013). Since NT-proBNP has been proposed as an indicator for HF follow-up therapy and prognosis (Olsson et al. 2007, Lainchbury et al. 2009), the parallel association of FABP4 and NT-proBNP supports the role of FABP4 as an HF biomarker (Cabre et al. 2013). Actually, an association between the FABP4 and NT-proBNP plasma levels was also found during treatment and follow-up, suggesting that an improvement in HF status was associated with a reduction in both the NT-proBNP and FABP4 concentrations (Cabre et al. 2013). Moreover, a large-scale prospective study reported that the FABP4 plasma levels predicted a higher risk of HF during a median follow-up period of 10.7 years (Djousse et al. 2013). However, while some authors support that FABP4 is directly associated with heart function (Liu et al. 2013), data from other studies suggest that circumstances other than myocardial function determine the association between FABP4 and HF markers (Cabre et al. 2013, Djousse et al. 2013). Thus, these contradictory data initially proposed FABP4 as a biomarker rather than as an aetiological agent in HF development. Nevertheless, additional reports have suggested that FABP4 may also promote heart dysfunction through its direct action on cardiomyocytes. Increased FABP4 expression has been reported in human epicardial adipose tissue from metabolic syndrome patients (Vural et al. 2008), suggesting a paracrine effect on cardiac cells. Additionally, a recent study by Furuhashi and coworkers showed that FABP4 that is locally produced by epicardial/perivascular fat and macrophages contributes to the development of coronary atherosclerosis (Furuhashi et al. 2016), highlighting the potential paracrine role of this adipokine. Interestingly, Lamounier-Zepter showed that FABP4 induced a cardiodepressant effect in experimental models of isolated rat cardiomyocytes (Lamounier-Zepter et al. 2009, Lamounier-Zepter et al. 2015), thus showing the first evidence of a cause–effect relationship between FABP4 and cardiomyocyte physiology. Recently, it has been shown that FABP4 is also expressed in cardiomyocytes, and the overexpression of cardiac FABP4 exacerbates the cardiac hypertrophic response induced by pressure overload (Zhang et al. 2016). Conversely, FABP4 deficiency attenuates ischaemia-/reperfusion-induced myocardial injury and improves LV function in both non-diabetic and streptozotocin-induced diabetic mice (Zhou et al. 2015). Therefore, FABP4 secreted from epicardial fat tissue, subcutaneous and/or visceral adipose tissue or macrophages may influence heart dysfunction in a paracrine or endocrine manner. However, the underlying molecular mechanisms by which FABP4 regulates cardiomyocyte function are only just beginning to emerge.
FABP4 and the cardiac fuel supply
Given the role of FABP4 as an FA carrier, the effect of this protein on cardiomyocyte contraction and myocardial remodelling may be by regulating substrate uptake for energy production in cardiomyocytes. Interestingly, the energy requirements in a healthy heart are mainly met by FAs (70%) (Gray & Kim 2011) and, to a lesser extent, glucose (20%), with lactate and ketone bodies composing the remainder of the fuel sources for the heart (Huss & Kelly 2005, Lopaschuk et al. 2010). Substrate uptake from the circulation to cardiomyocytes is a process that is carefully regulated by capillary endothelial cells (ECs). Compared to sinusoidal ECs that have large fenestrations that allow for the passage of particles that include albumin and chylomicron remnants, FA transport in the capillary ECs from the heart involves proteins with a high affinity for FA in the capillary endothelial cytoplasm (van der Vusse et al. 2000, van der Vusse 2009). Thus, FABP4 may contribute to the dysregulation of cardiac metabolic disorders, leading to deficient contractile function and HF by regulating the transport of the external supply of substrates, such as FAs, to cardiomyocytes (Fig. 3). Actually, both FABP4 and FABP5 have been found to be expressed in capillary ECs in several tissues, including the heart (Masouye et al. 1997, Elmasri et al. 2009), suggesting that both molecules may have redundant roles in regulating transendothelial FA transport. Specifically, using FABP4/5 double-knockout mice (Fabp4/5 DKO), Iso and coworkers showed that these molecules are essential for the regulation of substrate uptake into the heart. Although FA uptake was reduced in the Fabp4/5 DKO compared with that in wild-type mice, glucose uptake was remarkably increased (Iso et al. 2013). Since FABP4 is transcriptionally regulated by PPARγ, this nuclear receptor may contribute to transendothelial FA transport by regulating FABP4 and other FA transporters in ECs (Kanda et al. 2009, Goto et al. 2013). PPARγ activation induced FA uptake into human cardiac microvessel ECs via the transcriptional regulation of both FABP4 and fatty acid translocase (FAT)/CD36 (Goto et al. 2013). Interestingly, knockdown of either FABP4 or CD36 partially inhibited the effect of PPARγ-induced FA uptake, suggesting that both PPARγ targets are involved in this process (Goto et al. 2013). Nevertheless, further research is required to fully clarify the role of FABP4 in regulating substrate uptake and its subsequent utilisation in the heart.
FABP4 as a potential therapeutic target for HF and CVD
Given that FABP4 has been proposed as a contributor for the development of metabolic-related CVD, pharmacological regulation of this molecule may be considered as a potential therapeutic approach for treating CVD and HF. Since individuals with decreased FABP4 expression show a reduced risk of CVD (Tuncman et al. 2006), strategies have been focused on inhibiting or reducing the circulating levels of FABP4. In a US Food and Drug Administration (FDA) screen for approved drug repurposing, several drugs were discovered as FABP4-binding molecules, including the broad-spectrum antibiotic levofloxacin as a high-affinity FABP4 inhibitor, among others (Wang et al. 2014). Additionally, several synthetic FABP4 inhibitors have been developed to date (Lehmann et al. 2004, Ringom et al. 2004, Sulsky et al. 2007, Furuhashi & Hotamisligil 2008, Barf et al. 2009, Hertzel et al. 2009, Lan et al. 2011, Liu et al. 2011, Xu et al. 2012, Chen et al. 2014). Among them, BMS309403, an active small molecule that impedes the binding of FAs to the FABP4 FA-binding cavity (Furuhashi et al. 2007, Sulsky et al. 2007, Furuhashi & Hotamisligil 2008), has been shown in several experimental models to protect against insulin resistance, diabetes mellitus, fatty liver disease and atherosclerosis (Furuhashi et al. 2007, Lee et al. 2011). Additionally, HTS01037, another FABP4 inhibitor, attenuated the proinflammatory profile in macrophages (Xu et al. 2015), showing the potential effect of FABP4 inhibitors on inflammation-related diseases. Other approaches have targeted circulating FABP4 using neutralising antibodies as well as improving insulin sensitivity and glucose homeostasis (Cao et al. 2013, Miao et al. 2015). Similar effects were found by directly targeting FABP4 expression with short-hairpin RNAs (shRNAs) in adipose tissue from obese diabetic mice (Won et al. 2014). Thus, although further studies are needed to determine the efficacy and safety of FABP4 inhibitors for clinical use, the experimental evidence strongly supports FABP4 inhibition as an emerging approach for the treatment of CVD-related metabolic diseases.
Conclusions
Recent studies have identified FABP4 as a novel adipokine that is involved in HF and CVD. FABP4 has been associated with several components of metabolic syndrome, atherosclerosis, insulin resistance and low-grade inflammation, and thus, it has been proposed as a cardiometabolic predictor for CVD. Additionally, FABP4 has been directly related to cardiac alterations, and it is directly related to well-established hallmarks for HF, such as NT-proBNP. Thus, it has been proposed as an independent predictor for HF. Experimental studies support that FABP4 directly contributes to altered cardiac function. However, the underlying molecular mechanisms involved in the FABP4-induced cardiac dysfunction are only just beginning to emerge. It has been proposed that FABP4 controls myocardial function by regulating the transendothelial fuel supply to cardiomyocytes. Nevertheless, the role of FABP4 has not been explored in insulin-resistant cardiomyocytes/hearts. It is currently unknown whether FABP4 may regulate cellular signalling in the absence of fatty acids in cardiac cells. In addition, it is not clear if this molecule can be internalised by cardiomyocytes and take part in the regulation of cellular responses, such as inflammation, lipid oxidation or lipid droplets storage, among other processes. Although further research is required to fully understand the role of FABP4 in cardiac regulation, the evidence reviewed here supports the claim that this molecule is a potential target for new therapeutic strategies against cardiac disturbances that lead to HF.
Despite evidence supporting that pharmacological inhibition of FABP4 confers protection towards several metabolic-related disturbances, different aspects should be addressed before considering FABP4 inhibition as a realistic option for the treatment of CVD and HF. First, FABP4 inhibitors have not been explored in experimental models of HF. Apart from the potential effects of the FABP4 inhibitors on preventing/improving HF, additional studies must be done to determine the safety of these drugs. Therefore, to fully exploit the potential of FABP4 inhibitors for the therapeutic intervention against CVD and HF, the pharmaceutical industry will have to employ new drug development strategies to guarantee the efficacy and safety of these molecules.
In summary, while FABP4 has been identified as a novel molecule related to HF and CVD, further research is warranted to fully understand the role of this molecule in the cellular responses underlying these processes. Additionally, there are still some concerns regarding the development of selective and safe FABP4 inhibitors. Although data from preclinical studies seem promising, the development of new drugs is required before FABP4 inhibition can be considered a realistic therapeutic approach for the clinical treatment of HF and CVD.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This research was financially supported by a grant from ISCIII, Madrid, Spain (PI15/00627), and from the CIBER in Diabetes and Associated Metabolic Disorders (CB07/08/0028).
References
Adida A & Spener F 2006 Adipocyte-type fatty acid-binding protein as inter-compartmental shuttle for peroxisome proliferator activated receptor gamma agonists in cultured cell. Biochimica et Biophysica Acta 1761 172–181. (doi:10.1016/j.bbalip.2006.02.006)
Agardh HE, Folkersen L, Ekstrand J, Marcus D, Swedenborg J, Hedin U, Gabrielsen A & Paulsson-Berne G 2011 Expression of fatty acid-binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis. Journal of Internal Medicine 269 200–210. (doi:10.1111/j.1365-2796.2010.02304.x)
Ayers SD, Nedrow KL, Gillilan RE & Noy N 2007 Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4. Biochemistry 46 6744–6752. (doi:10.1021/bi700047a)
Baessler A, Lamounier-Zepter V, Fenk S, Strack C, Lahmann C, Loew T, Schmitz G, Bluher M, Bornstein SR & Fischer M 2014 Adipocyte fatty acid-binding protein levels are associated with left ventricular diastolic dysfunction in morbidly obese subjects. Nutrition & Diabetes 4 e106. (doi:10.1038/nutd.2014.3)
Bagheri R, Qasim AN, Mehta NN, Terembula K, Kapoor S, Braunstein S, Schutta M, Iqbal N, Lehrke M & Reilly MP 2010 Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus. American Journal of Cardiology 106 1118–1123. (doi:10.1016/j.amjcard.2010.06.028)
Bahrami H, Bluemke DA, Kronmal R, Bertoni AG, Lloyd-Jones DM, Shahar E, Szklo M & Lima JA 2008 Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study. Journal of the American College of Cardiology 51 1775–1783. (doi:10.1016/j.jacc.2007.12.048)
Balci MM, Arslan U, Firat H, Kocaoglu I, Vural MG, Balci KG, Maden O, Gurbuz OA, Ardic S & Yeter E 2012 Serum levels of adipocyte fatty acid-binding protein are independently associated with left ventricular mass and myocardial performance index in obstructive sleep apnea syndrome. Journal of Investigative Medicine 60 1020–1026. (doi:10.2310/JIM.0b013e31826868f2)
Baldasseroni S, Mannucci E, Orso F, Di Serio C, Pratesi A, Bartoli N, Marella GA, Colombi C, Foschini A & Valoti P et al. 2012 Adiponectin in outpatients with coronary artery disease: independent predictors and relationship with heart failure. Nutrition, Metabolism & Cardiovascular Diseases 22 292–299. (doi:10.1016/j.numecd.2011.03.012)
Bao Y, Lu Z, Zhou M, Li H, Wang Y, Gao M, Wei M & Jia W 2011 Serum levels of adipocyte fatty acid-binding protein are associated with the severity of coronary artery disease in Chinese women. PLoS ONE 6 e19115. (doi:10.1371/journal.pone.0019115)
Barf T, Lehmann F, Hammer K, Haile S, Axen E, Medina C, Uppenberg J, Svensson S, Rondahl L & Lundback T 2009 N-Benzyl-indolo carboxylic acids: design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors. Bioorganic and Medicinal Chemistry Letters 19 1745–1748. (doi:10.1016/j.bmcl.2009.01.084)
Bernlohr DA, Bolanowski MA, Kelly TJ Jr. & Lane MD 1985a Evidence for an increase in transcription of specific mRNAs during differentiation of 3T3-L1 preadipocytes. Journal of Biological Chemistry 260 5563–5567.
Bernlohr DA, Doering TL, Kelly TJ Jr. & Lane MD 1985b Tissue specific expression of p422 protein, a putative lipid carrier, in mouse adipocytes. Biochemical and Biophysical Research Communications 132 850–855. (doi:10.1016/0006-291X(85)91209-4)
Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF & Hotamisligil GS 2004 Combined adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice. Circulation 110 1492–1498. (doi:10.1161/01.CIR.0000141735.13202.B6)
Britton KA & Fox CS 2011 Ectopic fat depots and cardiovascular disease. Circulation 124 e837–e841. (doi:10.1161/CIRCULATIONAHA.111.077602)
Cabre A, Lazaro I, Girona J, Manzanares JM, Marimon F, Plana N, Heras M & Masana L 2007 Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients. Atherosclerosis 195 e150–e158. (doi:10.1016/j.atherosclerosis.2007.04.045)
Cabre A, Valdovinos P, Lazaro I, Bonet G, Bardaji A & Masana L 2013 Parallel evolution of circulating FABP4 and NT-proBNP in heart failure patients. Cardiovascular Diabetology 12 72. (doi:10.1186/1475-2840-12-72)
Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, Inouye K, Rickey LM, Ercal BC & Furuhashi M et al. 2013 Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metabolism 17 768–778. (doi:10.1016/j.cmet.2013.04.012)
Chen J, Wang J & Zhu W 2014 Binding modes of three inhibitors 8CA, F8A and I4A to A-FABP studied based on molecular dynamics simulation. PLoS ONE 9 e99862. (doi:10.1371/journal.pone.0099862)
Chmurzynska A 2006 The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. Journal of Applied Genetics 47 39–48. (doi:10.1007/BF03194597)
Chow WS, Tso AW, Xu A, Yuen MM, Fong CH, Lam TH, Lo SV, Tse HF, Woo YC & Yeung CY et al. 2013 Elevated circulating adipocyte-fatty acid binding protein levels predict incident cardiovascular events in a community-based cohort: a 12-year prospective study. Journal of the American Heart Association 2 e004176. (doi:10.1161/jaha.112.004176)
Christy RJ, Yang VW, Ntambi JM, Geiman DE, Landschulz WH, Friedman AD, Nakabeppu Y, Kelly TJ & Lane MD 1989 Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes. Genes and Development 3 1323–1335. (doi:10.1101/gad.3.9.1323)
Coe NR & Bernlohr DA 1998 Physiological properties and functions of intracellular fatty acid-binding proteins. Biochimica et Biophysica Acta 1391 287–306. (doi:10.1016/S0005-2760(97)00205-1)
Coe NR, Simpson MA & Bernlohr DA 1999 Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. Journal of Lipid Research 40 967–972.
Cook C, Cole G, Asaria P, Jabbour R & Francis DP 2014 The annual global economic burden of heart failure. International Journal of Cardiology 171 368–376. (doi:10.1016/j.ijcard.2013.12.028)
Djousse L, Bartz TM, Ix JH, Kochar J, Kizer JR, Gottdiener JS, Tracy RP, Mozaffarian D, Siscovick DS & Mukamal KJ et al. 2013 Fatty acid-binding protein 4 and incident heart failure: the cardiovascular health study. European Journal of Heart Failure 15 394–399. (doi:10.1093/eurjhf/hfs196)
Doi M, Miyoshi T, Hirohata S, Nakamura K, Usui S, Takeda K, Iwamoto M, Kusachi S, Kusano K & Ito H 2011 Association of increased plasma adipocyte fatty acid-binding protein with coronary artery disease in non-elderly men. Cardiovascular Diabetology 10 44. (doi:10.1186/1475-2840-10-44)
Ek BA, Cistola DP, Hamilton JA, Kaduce TL & Spector AA 1997 Fatty acid binding proteins reduce 15-lipoxygenase-induced oxygenation of linoleic acid and arachidonic acid. Biochimica et Biophysica Acta 1346 75–85. (doi:10.1016/S0005-2760(97)00021-0)
Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J & Cataltepe S 2009 Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB Journal 23 3865–3873. (doi:10.1096/fj.09-134882)
Engeli S, Utz W, Haufe S, Lamounier-Zepter V, Pofahl M, Traber J, Janke J, Luft FC, Boschmann M & Schulz-Menger J et al. 2013 Fatty acid binding protein 4 predicts left ventricular mass and longitudinal function in overweight and obese women. Heart 99 944–948. (doi:10.1136/heartjnl-2013-303735)
Forman DE, Cannon CP, Hernandez AF, Liang L, Yancy C & Fonarow GC 2009 Influence of age on the management of heart failure: findings from get with the guidelines-heart failure (GWTG-HF). American Heart Journal 157 1010–1017. (doi:10.1016/j.ahj.2009.03.010)
Fu Y, Luo N & Lopes-Virella MF 2000 Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. Journal of Lipid Research 41 2017–2023.
Fu Y, Luo N, Lopes-Virella MF & Garvey WT 2002 The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. Atherosclerosis 165 259–269.
Furuhashi M & Hotamisligil GS 2008 Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nature Reviews Drug Discovery 7 489–503. (doi:10.1038/nrd2589)
Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S & Linton MF et al. 2007 Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447 959–965. (doi:10.1038/nature05844)
Furuhashi M, Ishimura S, Ota H & Miura T 2011 Lipid chaperones and metabolic inflammation. International Journal of Inflammation 2011 642612. (doi:10.4061/2011/642612)
Furuhashi M, Fuseya T, Murata M, Hoshina K, Ishimura S, Mita T, Watanabe Y, Omori A, Matsumoto M & Sugaya T et al. 2016 Local production of fatty acid-binding protein 4 in epicardial/perivascular fat and macrophages is linked to coronary atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 36 825–834. (doi:10.1161/ATVBAHA.116.307225)
Fuseya T, Furuhashi M, Yuda S, Muranaka A, Kawamukai M, Mita T, Ishimura S, Watanabe Y, Hoshina K & Tanaka M et al. 2014 Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population. Cardiovascular Diabetology 13 126. (doi:10.1186/s12933-014-0126-7)
Gillilan RE, Ayers SD & Noy N 2007 Structural basis for activation of fatty acid-binding protein 4. Journal of Molecular Biology 372 1246–1260. (doi:10.1016/j.jmb.2007.07.040)
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS & Franco S et al. 2014 Executive summary: heart disease and stroke statistics – 2014 update: a report from the american heart association. Circulation 129 399–410. (doi:10.1161/01.cir.0000442015.53336.12)
Goto K, Iso T, Hanaoka H, Yamaguchi A, Suga T, Hattori A, Irie Y, Shinagawa Y, Matsui H & Syamsunarno MR et al. 2013 Peroxisome proliferator-activated receptor-gamma in capillary endothelia promotes fatty acid uptake by heart during long-term fasting. Journal of the American Heart Association 2 e004861. (doi:10.1161/jaha.112.004861)
Graner M, Pentikainen MO, Nyman K, Siren R, Lundbom J, Hakkarainen A, Lauerma K, Lundbom N, Nieminen MS & Petzold M et al. 2014 Cardiac steatosis in patients with dilated cardiomyopathy. Heart 100 1107–1112. (doi:10.1136/heartjnl-2013-304961)
Gray S & Kim JK 2011 New insights into insulin resistance in the diabetic heart. Trends in Endocrinology and Metabolism 22 394–403. (doi:10.1016/j.tem.2011.05.001)
Hertzel AV, Hellberg K, Reynolds JM, Kruse AC, Juhlmann BE, Smith AJ, Sanders MA, Ohlendorf DH, Suttles J & Bernlohr DA 2009 Identification and characterization of a small molecule inhibitor of fatty acid binding proteins. Journal of Medicinal Chemistry 52 6024–6031. (doi:10.1021/jm900720m)
Holm S, Ueland T, Dahl TB, Michelsen AE, Skjelland M, Russell D, Nymo SH, Krohg-Sorensen K, Clausen OP & Atar D et al. 2011 Fatty acid binding protein 4 is associated with carotid atherosclerosis and outcome in patients with acute ischemic stroke. PLoS ONE 6 e28785. (doi:10.1371/journal.pone.0028785)
Hu G, Jousilahti P, Antikainen R, Katzmarzyk PT & Tuomilehto J 2010 Joint effects of physical activity, body mass index, waist circumference, and waist-to-hip ratio on the risk of heart failure. Circulation 121 237–244. (doi:10.1161/CIRCULATIONAHA.109.887893)
Huang CL, Wu YW, Wu CC, Lin L, Wu YC, Hsu PY, Jong YS & Yang WS 2013 Association between serum adipocyte fatty-acid binding protein concentrations, left ventricular function and myocardial perfusion abnormalities in patients with coronary artery disease. Cardiovascular Diabetology 12 105. (doi:10.1186/1475-2840-12-105)
Hui X, Li H, Zhou Z, Lam KS, Xiao Y, Wu D, Ding K, Wang Y, Vanhoutte PM & Xu A 2010 Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1. Journal of Biological Chemistry 285 10273–10280. (doi:10.1074/jbc.M109.097907)
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM & Michl K et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults a report of the American college of cardiology foundation/American heart association task force on practice guidelines developed in collaboration with the international society for heart and lung transplantation. Journal of the American College of Cardiology 53 e1–e90. (doi:10.1016/j.jacc.2008.11.013)
Huss JM & Kelly DP 2005 Mitochondrial energy metabolism in heart failure: a question of balance. Journal of Clinical Investigation 115 547–555. (doi:10.1172/JCI24405)
Ingelsson E, Sundstrom J, Arnlov J, Zethelius B & Lind L 2005 Insulin resistance and risk of congestive heart failure. JAMA 294 334–341. (doi:10.1001/jama.294.3.334)
Ishimura S, Furuhashi M, Watanabe Y, Hoshina K, Fuseya T, Mita T, Okazaki Y, Koyama M, Tanaka M & Akasaka H et al. 2013 Circulating levels of fatty acid-binding protein family and metabolic phenotype in the general population. PLoS ONE 8 e81318. (doi:10.1371/journal.pone.0081318)
Iso T, Maeda K, Hanaoka H, Suga T, Goto K, Syamsunarno MR, Hishiki T, Nagahata Y, Matsui H & Arai M et al. 2013 Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arteriosclerosis, Thrombosis, and Vascular Biology 33 2549–2557. (doi:10.1161/ATVBAHA.113.301588)
Kaess BM, Enserro DM, McManus DD, Xanthakis V, Chen MH, Sullivan LM, Ingram C, O’Donnell CJ, Keaney JF & Vasan RS et al. 2012 Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study. Journal of Clinical Endocrinology and Metabolism 97 E1943–E1947. (doi:10.1210/jc.2012-1458)
Kanda T, Brown JD, Orasanu G, Vogel S, Gonzalez FJ, Sartoretto J, Michel T & Plutzky J 2009 PPARgamma in the endothelium regulates metabolic responses to high-fat diet in mice. Journal of Clinical Investigation 119 110–124. (doi:10.1172/JCI36233)
Kazemi MR, McDonald CM, Shigenaga JK, Grunfeld C & Feingold KR 2005 Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arteriosclerosis, Thrombosis, and Vascular Biology 25 1220–1224. (doi:10.1161/01.ATV.0000159163.52632.1b)
Kenchaiah S, Sesso HD & Gaziano JM 2009 Body mass index and vigorous physical activity and the risk of heart failure among men. Circulation 119 44–52. (doi:10.1161/CIRCULATIONAHA.108.807289)
Kershaw EE & Flier JS 2004 Adipose tissue as an endocrine organ. Journal of Clinical Endocrinology and Metabolism 89 2548–2556. (doi:10.1210/jc.2004-0395)
Kletzien RF, Foellmi LA, Harris PK, Wyse BM & Clarke SD 1992 Adipocyte fatty acid-binding protein: regulation of gene expression in vivo and in vitro by an insulin-sensitizing agent. Molecular Pharmacology 42 558–562.
Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A, Yandle TG, Hamid AK, Nicholls MG & Richards AM 2009 N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. Journal of the American College of Cardiology 55 53–60. (doi:10.1016/j.jacc.2009.02.095)
LaLonde JM, Bernlohr DA & Banaszak LJ 1994 X-ray crystallographic structures of adipocyte lipid-binding protein complexed with palmitate and hexadecanesulfonic acid. Properties of cavity binding sites. Biochemistry 33 4885–4895. (doi:10.1021/bbib182a017)
Lamounier-Zepter V, Look C, Alvarez J, Christ T, Ravens U, Schunck WH, Ehrhart-Bornstein M, Bornstein SR & Morano I 2009 Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity and heart disease. Circulation Research 105 326–334. (doi:10.1161/CIRCRESAHA.109.200501)
Lamounier-Zepter V, Look C, Schunck WH, Schlottmann I, Woischwill C, Bornstein SR, Xu A & Morano I 2015 Interaction of epoxyeicosatrienoic acids and adipocyte fatty acid-binding protein in the modulation of cardiomyocyte contractility. International Journal of Obesity 39 755–761. (doi:10.1038/ijo.2014.193)
Lan H, Cheng CC, Kowalski TJ, Pang L, Shan L, Chuang CC, Jackson J, Rojas-Triana A, Bober L & Liu L et al. 2011 Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity. Journal of Lipid Research 52 646–656. (doi:10.1194/jlr.M012757)
Lavie CJ, Milani RV & Ventura HO 2009 Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. Journal of the American College of Cardiology 53 1925–1932. (doi:10.1016/j.jacc.2008.12.068)
Lee MY, Li H, Xiao Y, Zhou Z, Xu A & Vanhoutte PM 2011 Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells. British Pharmacological Society 162 1564–1576. (doi:10.1111/j.1476-5381.2010.01158.x)
Lee K, Santibanez-Koref M, Polvikoski T, Birchall D, Mendelow AD & Keavney B 2013 Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture. Atherosclerosis 226 74–81. (doi:10.1016/j.atherosclerosis.2012.09.037)
Lehmann F, Haile S, Axen E, Medina C, Uppenberg J, Svensson S, Lundback T, Rondahl L & Barf T 2004 Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorganic & Medicinal Chemistry Letters 14 4445–4448. (doi:10.1016/j.bmcl.2004.06.057)
Liu X, Huang X, Lin W, Wang D, Diao Y, Li H, Hui X, Wang Y, Xu A & Wu D et al. 2011 New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein. Bioorganic and Medicinal Chemistry Letters 21 2949–2952. (doi:10.1016/j.bmcl.2011.03.063)
Liu M, Zhou M, Bao Y, Xu Z, Li H, Zhang H, Zhu W, Zhang J, Xu A & Wei M et al. 2013 Circulating adipocyte fatty acid-binding protein levels are independently associated with heart failure. Clinical Science 124 115–122. (doi:10.1042/CS20120004)
Liu G, Ding M, Chiuve SE, Rimm EB, Franks PW, Meigs JB, Hu FB & Sun Q 2016 Plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, high-molecular-weight adiponectin, and cardiovascular mortality among men with type 2 diabetes: a 22-year prospective study. Arteriosclerosis, Thrombosis, and Vascular Biology 36 2259–2267. (doi:10.1161/ATVBAHA.116.308320)
Loehr LR, Rosamond WD, Chang PP, Folsom AR & Chambless LE 2008 Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study). American Journal of Cardiology 101 1016–1022. (doi:10.1016/j.amjcard.2007.11.061)
Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS & Stanley WC 2010 Myocardial fatty acid metabolism in health and disease. Physiological Reviews 90 207–258. (doi:10.1152/physrev.00015.2009)
Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S & Hotamisligil GS et al. 2001 Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nature Medicine 7 699–705. (doi:10.1038/89076)
Makowski L, Brittingham KC, Reynolds JM, Suttles J & Hotamisligil GS 2005 The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. Journal of Biological Chemistry 280 12888–12895. (doi:10.1074/jbc.M413788200)
Marr E, Tardie M, Carty M, Brown Phillips T, Wang IK, Soeller W, Qiu X & Karam G 2006 Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2). Acta Crystallographica Section F Structural Biology and Crystallization Communications 62 1058–1060. (doi:10.1107/S1744309106038656)
Masouye I, Hagens G, Van Kuppevelt TH, Madsen P, Saurat JH, Veerkamp JH, Pepper MS & Siegenthaler G 1997 Endothelial cells of the human microvasculature express epidermal fatty acid-binding protein. Circulation Research 81 297–303. (doi:10.1161/01.RES.81.3.297)
Miao X, Wang Y, Wang W, Lv X, Wang M & Yin H 2015 The mAb against adipocyte fatty acid-binding protein 2E4 attenuates the inflammation in the mouse model of high-fat diet-induced obesity via toll-like receptor 4 pathway. Molecular and Cellular Endocrinology 403 1–9. (doi:10.1016/j.mce.2014.12.017)
Mita T, Furuhashi M, Hiramitsu S, Ishii J, Hoshina K, Ishimura S, Fuseya T, Watanabe Y, Tanaka M & Ohno K et al. 2015 FABP4 is secreted from adipocytes by adenyl cyclase-PKA- and guanylyl cyclase-PKG-dependent lipolytic mechanisms. Obesity 23 359–367. (doi:10.1002/oby.20954)
Miyoshi T, Onoue G, Hirohata A, Hirohata S, Usui S, Hina K, Kawamura H, Doi M, Kusano KF & Kusachi S et al. 2010 Serum adipocyte fatty acid-binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound. Atherosclerosis 211 164–169. (doi:10.1016/j.atherosclerosis.2010.01.032)
Morkedal B, Vatten LJ, Romundstad PR, Laugsand LE & Janszky I 2014 Risk of myocardial infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-Trondelag Health Study), Norway. Journal of the American College of Cardiology 63 1071–1078. (doi:10.1016/j.jacc.2013.11.035)
Mosterd A & Hoes AW 2007 Clinical epidemiology of heart failure. Heart 93 1137–1146. (doi:10.1136/hrt.2003.025270)
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ & Howard VJ et al. 2015 Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 131 e29–e322. (doi:10.1161/CIR.0000000000000152)
Neumann T, Biermann J, Erbel R, Neumann A, Wasem J, Ertl G & Dietz R 2009 Heart failure: the commonest reason for hospital admission in Germany: medical and economic perspectives. Deutsches Ärzteblatt International 106 269–275. (doi:10.3238/arztebl.2009.0269)
Olsson LG, Swedberg K, Cleland JG, Spark PA, Komajda M, Metra M, Torp-Pedersen C, Remme WJ, Scherhag A & Poole-Wilson P et al. 2007 Prognostic importance of plasma NT-pro BNP in chronic heart failure in patients treated with a beta-blocker: results from the Carvedilol Or Metoprolol European Trial (COMET) trial. European Journal of Heart Failure 9 795–801. (doi:10.1016/j.ejheart.2007.07.010)
Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM & McAlister FA 2008 Body mass index and mortality in heart failure: a meta-analysis. American Heart Journal 156 13–22. (doi:10.1016/j.ahj.2008.02.014)
Peeters W, de Kleijn DP, Vink A, van de Weg S, Schoneveld AH, Sze SK, van der Spek PJ, de Vries JP, Moll FL & Pasterkamp G 2011 Adipocyte fatty acid binding protein in atherosclerotic plaques is associated with local vulnerability and is predictive for the occurrence of adverse cardiovascular events. European Heart Journal 32 1758–1768. (doi:10.1093/eurheartj/ehq387)
Pelton PD, Zhou L, Demarest KT & Burris TP 1999 PPARgamma activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. Biochemical and Biophysical Research Communications 261 456–458. (doi:10.1006/bbrc.1999.1071)
Reiser H, Klingenberg R, Hof D, Cooksley-Decasper S, Fuchs N, Akhmedov A, Zoller S, Marques-Vidal P, Marti Soler H & Heg D et al. 2015 Circulating FABP4 is a prognostic biomarker in patients with acute coronary syndrome but not in asymptomatic individuals. Arteriosclerosis, Thrombosis, and Vascular Biology 35 1872–1879. (doi:10.1161/ATVBAHA.115.305365)
Rhee EJ, Lee WY, Park CY, Oh KW, Kim BJ, Sung KC & Kim BS 2009 The association of serum adipocyte fatty acid-binding protein with coronary artery disease in Korean adults. European Journal of Endocrinology 160 165–172. (doi:10.1530/EJE-08-0665)
Ringom R, Axen E, Uppenberg J, Lundback T, Rondahl L & Barf T 2004 Substituted benzylamino-6-(trifluoromethyl)pyrimidin-4(1H)-ones: a novel class of selective human A-FABP inhibitors. Bioorganic and Medicinal Chemistry Letters 14 4449–4452. (doi:10.1016/j.bmcl.2004.06.058)
Rolph MS, Young TR, Shum BO, Gorgun CZ, Schmitz-Peiffer C, Ramshaw IA, Hotamisligil GS & Mackay CR 2006 Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. Journal of Immunology 177 7794–7801. (doi:10.4049/jimmunol.177.11.7794)
Scheja L, Makowski L, Uysal KT, Wiesbrock SM, Shimshek DR, Meyers DS, Morgan M, Parker RA & Hotamisligil GS 1999 Altered insulin secretion associated with reduced lipolytic efficiency in aP2−/− mice. Diabetes 48 1987–1994. (doi:10.2337/diabetes.48.10.1987)
Shah R, Gayat E, Januzzi JL Jr., Sato N, Cohen-Solal A, di Somma S, Fairman E, Harjola VP, Ishihara S & Lassus J et al. 2014 Body mass index and mortality in acutely decompensated heart failure across the world: a global obesity paradox. Journal of the American College of Cardiology 63 778–785. (doi:10.1016/j.jacc.2013.09.072)
Shen WJ, Sridhar K, Bernlohr DA & Kraemer FB 1999 Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. PNAS 96 5528–5532. (doi:10.1073/pnas.96.10.5528)
Shen WJ, Liang Y, Hong R, Patel S, Natu V, Sridhar K, Jenkins A, Bernlohr DA & Kraemer FB 2001 Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase. Journal of Biological Chemistry 276 49443–49448. (doi:10.1074/jbc.M104095200)
Smith PJ, Wise LS, Berkowitz R, Wan C & Rubin CS 1988 Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. Journal of Biological Chemistry 263 9402–9408.
Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S & McMurray JJ 2002 The current cost of heart failure to the National Health Service in the UK. European Journal of Heart Failure 4 361–371. (doi:10.1016/S1388-9842(01)00198-2)
Sulsky R, Magnin DR, Huang Y, Simpkins L, Taunk P, Patel M, Zhu Y, Stouch TR, Bassolino-Klimas D & Parker R et al. 2007 Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorganic & Medicinal Chemistry Letters 17 3511–3515. (doi:10.1016/j.bmcl.2006.12.044)
Tang WH, Francis GS, Morrow DA, Newby LK, Cannon CP, Jesse RL, Storrow AB, Christenson RH, Apple FS & Ravkilde J et al. 2007 National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines: Clinical utilization of cardiac biomarker testing in heart failure. Circulation 116 e99–e109. (doi:10.1161/CIRCULATIONAHA.107.185267)
Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, Cheung BM, Janus ED & Lam KS 2007 Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care 30 2667–2672. (doi:10.2337/dbib7-0413)
Tso AW, Lam TK, Xu A, Yiu KH, Tse HF, Li LS, Law LS, Cheung BM, Cheung RT & Lam KS 2011 Serum adipocyte fatty acid-binding protein associated with ischemic stroke and early death. Neurology 76 1968–1975. (doi:10.1212/WNL.0b013e31821e54b3)
Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB & Hotamisligil GS 2006 A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. PNAS 103 6970–6975. (doi:10.1073/pnas.0602178103)
van der Vusse GJ 2009 Albumin as fatty acid transporter. Drug Metabolism and Pharmacokinetics 24 300–307. (doi:10.2133/dmpk.24.300)
van der Vusse GJ, van Bilsen M & Glatz JF 2000 Cardiac fatty acid uptake and transport in health and disease. Cardiovascular Research 45 279–293. (doi:10.1016/S0008-6363(99)00263-1)
von Eynatten M, Breitling LP, Roos M, Baumann M, Rothenbacher D & Brenner H 2012 Circulating adipocyte fatty acid-binding protein levels and cardiovascular morbidity and mortality in patients with coronary heart disease: a 10-year prospective study. Arteriosclerosis, Thrombosis, and Vascular Biology 32 2327–2335. (doi:10.1161/ATVBAHA.112.248609)
Voulgari C, Tentolouris N, Dilaveris P, Tousoulis D, Katsilambros N & Stefanadis C 2011 Increased heart failure risk in normal-weight people with metabolic syndrome compared with metabolically healthy obese individuals. Journal of the American College of Cardiology 58 1343–1350. (doi:10.1016/j.jacc.2011.04.047)
Vural B, Atalar F, Ciftci C, Demirkan A, Susleyici-Duman B, Gunay D, Akpinar B, Sagbas E, Ozbek U & Buyukdevrim AS 2008 Presence of fatty-acid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovascular Pathology 17 392–398. (doi:10.1016/j.carpath.2008.02.006)
Wang J, Sarnola K, Ruotsalainen S, Moilanen L, Lepisto P, Laakso M & Kuusisto J 2010 The metabolic syndrome predicts incident congestive heart failure: a 20-year follow-up study of elderly Finns. Atherosclerosis 210 237–242. (doi:10.1016/j.atherosclerosis.2009.10.042)
Wang XQ, Yang K, He YS, Lu L & Shen WF 2011 Receptor mediated elevation in FABP4 levels by advanced glycation end products induces cholesterol and triacylglycerol accumulation in THP-1 macrophages. Lipids 46 479–486. (doi:10.1007/s11745-011-3542-4)
Wang Y, Law WK, Hu JS, Lin HQ, Ip TM & Wan DC 2014 Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening. Journal of Chemical Information and Modeling 54 3046–3050. (doi:10.1021/ci500503b)
Won YW, Adhikary PP, Lim KS, Kim HJ, Kim JK & Kim YH 2014 Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nature Materials 13 1157–1164. (doi:10.1038/nmat4092)
Writing Group Members Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E & Furie K et al. 2010 Heart disease and stroke statistics – 2010 update: a report from the American Heart Association. Circulation 121 e46–e215. (doi:10.1161/CIRCULATIONAHA.109.192667)
Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, Wat NM, Wong WK & Lam KS 2006 Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clinical Chemistry 52 405–413. (doi:10.1373/clinchem.2005.062463)
Xu A, Tso AW, Cheung BM, Wang Y, Wat NM, Fong CH, Yeung DC, Janus ED, Sham PC & Lam KS 2007 Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation 115 1537–1543. (doi:10.1161/CIRCULATIONAHA.106.647503)
Xu A, Wang Y, Lam KS & Vanhoutte PM 2010 Vascular actions of adipokines molecular mechanisms and therapeutic implications. Advances in Pharmacology 60 229–255. (doi:10.1016/B978-0-12-385061-4.00008-8)
Xu Q, Huang L, Liu J, Ma L, Chen T, Chen J, Peng F, Cao D, Yang Z & Qiu N et al. 2012 Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes. European Journal of Medicinal Chemistry 52 70–81. (doi:10.1016/j.ejmech.2012.03.006)
Xu H, Hertzel AV, Steen KA, Wang Q, Suttles J & Bernlohr DA 2015 Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Molecular and Cellular Biology 35 1055–1065. (doi:10.1128/MCB.01122-14)
Yang VW, Christy RJ, Cook JS, Kelly TJ & Lane MD 1989 Mechanism of regulation of the 422(aP2) gene by cAMP during preadipocyte differentiation. PNAS 86 3629–3633. (doi:10.1073/pnas.86.10.3629)
Yeung DC, Xu A, Cheung CW, Wat NM, Yau MH, Fong CH, Chau MT & Lam KS 2007 Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 27 1796–1802. (doi:10.1161/ATVBAHA.107.146274)
Zamora E, Lupon J, Enjuanes C, Pascual-Figal D, de Antonio M, Domingo M, Comin-Colet J, Vila J, Penafiel J & Farre N et al. 2016 No benefit from the obesity paradox for diabetic patients with heart failure. European Journal of Heart Failure 18 851–858. (doi:10.1002/ejhf.576)
Zhang J, Qiao C, Chang L, Guo Y, Fan Y, Villacorta L, Chen YE & Zhang J 2016 Cardiomyocyte overexpression of FABP4 aggravates pressure overload-induced heart hypertrophy. PLoS ONE 11 e0157372. (doi:10.1371/journal.pone.0157372)
Zhou M, Bao Y, Li H, Pan Y, Shu L, Xia Z, Wu D, Lam KS, Vanhoutte PM & Xu A et al. 2015 Deficiency of adipocyte fatty-acid-binding protein alleviates myocardial ischaemia/reperfusion injury and diabetes-induced cardiac dysfunction. Clinical Science 129 547–559. (doi:10.1042/CS20150073)
Zimmer JS, Dyckes DF, Bernlohr DA & Murphy RC 2004 Fatty acid binding proteins stabilize leukotriene A4: competition with arachidonic acid but not other lipoxygenase products. Journal of Lipid Research 45 2138–2144. (doi:10.1194/jlr.M400240-JLR200)
Zimmerman AW & Veerkamp JH 2002 New insights into the structure and function of fatty acid-binding proteins. Cellular and Molecular Life Sciences 59 1096–1116. (doi:10.1007/s00018-002-8490-y)