肝脏X受体LXRα (NR1H3)和LXRβ (NR1H2)是核受体超家族成员，是配体激活的转录因子。NR1H2和NR1H3的天然配体是通过酶促反应、依赖活性氧(ROS)的胆固醇氧化和消化过程内源性产生的氧甾醇(如24(S)，25-环氧胆固醇，24(S)-羟基胆固醇(OH)， 25-OH和27-OH)(综述于:Jakobsson T et al. 2012;黄C 2014;Komati R et al. 2017)。研究表明，这些氧甾醇直接与LXRs的配体结合结构域结合，Kd值从0.1到0.4 microM不等。24(S)， 25环氧胆固醇被发现是最有效的内源性激动剂(Janowski BA et al. 1999)。NR1H3 (LXRα)和NR1H2 (LXRβ)对这些化合物表现出相似的亲和力(Janowski BA et al. 1999)。在生理条件下，细胞内形成的羟甾醇与胆固醇含量成正比，因此LXRs作为胆固醇传感器，通过以下途径改变基因表达，保护细胞免受胆固醇超载:(1)抑制肠道胆固醇吸收;(2)通过atp结合盒转运体ABCA1和ABCG1刺激胆固醇从细胞外排到高密度脂蛋白;(3)激活肝脏内胆固醇向胆汁酸的转化;(4)激活胆道胆固醇和胆汁酸排泄(综述于:Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J & Rydén M 2012; Edwards PA et al. 2002; Zelcer N & Tontonoz P 2006; Zhao C & Dahlman-Wright K 2010). In addition, LXR agonists enhance de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and hepatic steatosis (Wójcicka G et al. 2007; Baranowski M 2008; Laurencikiene J & Rydén M 2012). In addition to their function in lipid metabolism, NR1H2,3 have also been found to modulate immune and inflammatory responses in macrophages (Zelcer N & Tontonoz P 2006). The NR1H2 and NR1H3 molecules can be viewed as having four functional domains: (1) an amino-terminal ligand-independent activation function domain (AF-1), which may stimulate transcription in the absence of ligand; (2) a DNA-binding domain (DBD) containing two zinc fingers; (3) a hydrophobic ligand-binding domain (LBD) required for ligand binding and receptor dimerization; and, (4) a carboxy-terminal ligand-dependent transactivation sequence (also referred to as the activation function-2 (AF-2) domain) that stimulates transcription in response to ligand binding (Robinson-Rechavi M et al. 2003; Jakobsson T et al. 2012; Färnegardh M et al. 2003; Lin CY & Gustafsson JA 2015). Although both NR1H3 and NR1H2 are activated by the same ligands and are structurally similar, their tissue expression profiles are very different. NR1H3 is selectively expressed in specific tissues and cell types, such as the liver, intestine, adrenal gland, adipose tissue and macrophages, whereas NR1H2 is ubiquitously expressed (Nishimura M et al. 2004; Bookout AL et al. 2006). Upon activation NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF & Gustafsson JA 1997). An inverted repeat of the same consensus sequence with no spacer region(IR-0) and an inverted repeat of the same consensus sequence separated by a 1 bp spacer (IR-1) have also been shown to mediate LXR transactivation (Mak PA et al. 2002, Landrier JF et al. 2003). NR1H3 and NR1H2 have been shown to regulate gene expression via LXREs in the promoter regions of their target genes such as UDP glucuronosyltransferase 1 family, polypeptide A3 (UGT1A3) (Verreault M et al. 2006), fatty acid synthase (FAS) (Joseph SB et al. 2002a), carbohydrate response element binding protein (ChREBP, also known as MLX-interacting protein-like or MLXIPL) (Cha JY & Repa JJ 2007) and phospholipid transfer protein (PLTP) (Mak PA et al. 2002). LXREs have also been reported to be present in introns of target genes such as the ATP-binding cassette transporter G1 (ABCG1) (Sabol SL et al. 2005). NR1H3 has been shown to activate gene expression via the FXR-responsive element found in the proximal promoter of the human ileal bile acid-binding protein (FABP6) (Landrier JF et al. 2003). The NR1H2,3:RXR heterodimers are permissive, in that they can be activated by ligands for either NR1H2,3 (LXR) or RXR (Willy PJ et al. 1995).