The liver X receptors (LXRs) are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol. There are two isoforms of LXR, LXRα (NR1H3) and LXRβ (NR1H2). Both LXRα and LXRβ regulate gene expression by binding to DNA sequences associated with target genes as heterodimers with isoforms of the retinoid X receptor (RXR), RXRα (NR2B1), RXRβ (NR2B2), and RXRγ (NR2B3). LXRs act as cholesterol sensors: when cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, LXR induces the transcription of genes that protect cells from cholesterol overload. In this review, we summarize the roles of LXRs in controlling cholesterol homeostasis, including their roles in bile acid synthesis and metabolism/excretion, reverse cholesterol transport, cholesterol biosynthesis and uptake, and cholesterol absorption/excretion in the intestine. The overlapping and distinct roles of the LXRα and LXRβ isoforms, and the potential use of LXRs as attractive targets for treatment of cardiovascular disease are also discussed.
Chunyan Zhao and Karin Dahlman-Wright
Malin Hedengran Faulds, Chunyan Zhao, Karin Dahlman-Wright and Jan-Åke Gustafsson
The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic β cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.
Lovisa Lundholm, Milica Putnik, Michio Otsuki, Sandra Andersson, Claes Ohlsson, Jan-Åke Gustafsson and Karin Dahlman-Wright
Obesity has become a major health problem in many parts of the world. Estrogens are known to reduce adipose tissue mass in both humans and animals but the molecular mechanisms are not well characterized. We used gene expression profiling to study long-term effects of estrogen on gene expression in mouse white adipose tissue and hypothalamus. Overall, the effects of estrogen on hypothalamic gene expression were much smaller than the corresponding effects on white adipose tissue gene expression. We characterize in detail estrogenic regulation of glutathione peroxidase 3 (GPX3). Our studies suggest that GPX3 is a direct estrogen receptor α target gene in white adipose tissue. Since obesity is correlated with oxidative stress, and GPX3 has been demonstrated to be lower in obesity and higher after weight loss, we hypothesize that GPX3 is one important mediator of effects of estrogen in relation to fat mass. Additional genes that were affected by estrogen in adipose tissue include cell death-inducing DNA fragmentation factor, α-subunit-like effector A (CIDEA), a gene shown to be related to body fat in mice. We conclude that estrogen has large effects on gene expression in white adipose tissue and hypothesize that GPX3 and CIDEA could be important mediators of the effects of estrogen on fat mass.