Nuclear receptors

From LipidomicsWiki

Nuclear receptors are ligand-activated transcription factors that regulate many genes involved in cell growth, differentiation, and metabolism (Mangelsdorf et al. 1995; Kliewer 1999; Chawla 2001). There are 48 nuclear receptor genes in the human genome. Nuclear receptors that have no identifiable ligand are referred to as orphan receptors (Class II receptors) (Kliewer et al. 1999; Giguere 1999; Xie and Evans 2001). Potential ligands of several orphan receptors identified are small lipid metabolites. These ‘adopted’ receptors, including farnesoid X receptor (FXR), liver orphan receptor (LXR), and peroxisome proliferators-activated receptors (PPARs), form heterodimers with retinoid X receptor (RXR) and bind to direct repeats of AGGTCA-like sequences (Chawla et al. 2001). The nuclear receptor has a modular structure that consists of an N-terminal variable activation function 1 domain, a conserved Zn2+ finger DNA-binding domain, a hinge domain, a highly conserved ligand-binding domain, and a C-terminal activation function 2 domain. In general, a nuclear receptor binds to co-repressor in the absence of a ligand. Upon binding of a ligand, a nuclear receptor undergoes conformational changes and releases a co-repressor and recruits a coactivator to the AF2 domain and activates gene transcription (Glass et al. 1997; McKenna 1999). Three nuclear receptors have recently been identified as the bile acid-activated receptors. FXR regulates bile acid synthesis, transport and absorption, as well as reverse cholesterol transport (RCT) (Wang et al. 1999; Makashima et al. 1999; Parks et al. 1999). Pregnane X receptor (PXR), or its human ortholog, steroid and xenobiotic receptor (SXR) regulates lithocholic acid and drug metabolisms (Staudinger et al. 2001; Xie et al. 2001). Vitamin D receptor (VDR) regulates calcium and phosphate homeostasis (Makishima et al. 2002). Bile acid metabolites also activate LXRα, which is an oxysterol receptor that plays a central role in lipid metabolism (Forman et al. 1997; Janowski et al. 1999; Song et al. 2000; Handschin et al. 2002). Hepatocyte nuclear factor 4α (HNF4α) binds fatty acids and plays important roles in lipoprotein metabolism (Xanthopoulos 1991; Hayhurst et al. 2001). Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) (or apolipoprotein A1 regulatory protein-1) is an orphan receptor that regulates lipoprotein metabolism (Ladias and Karathanasis 1991; Ladias et al. 1992). Peroxisome proliferator-activated receptors (PPARα, γ, δ) are activated by fatty acids and fibrates and induce genes involved in fatty acid transport and oxidation, and energy metabolism in liver, muscle and adipocytes (Desvergne and Wahli 1999, Francis et al. 2003). These nuclear receptors regulate key bile acid biosynthetic genes (Chiang 2002), and have been referred to as the ‘metabolic receptors’ that coordinately regulates a network of genes involved in integrated control of energy metabolism, bile acid metabolism, lipoprotein metabolism, and triglyceride metabolism (Francis et al. 2003).

Other pages of this category: