NR1H2 and NR1H3-mediated signaling

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R-HSA-9024446
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Pathway
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Homo sapiens
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LXR-mediated signaling
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The liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor superfamily and function as ligand-activated transcription factors. The natural ligands of NR1H2 and NR1H3 are oxysterols (e.g., 24(S),25-epoxycholesterol, 24(S)-hydroxycholesterol (OH), 25-OH, and 27-OH) that are produced endogenously by enzymatic reactions, by reactive oxygen species (ROS)-dependent oxidation of cholesterol and by the alimentary processes (reviewed in:Jakobsson T et al. 2012; Huang C 2014; Komati R et al. 2017). It has been shown that these oxysterols bind directly to the ligand-binding domain of LXRs with Kd values ranging from 0.1 to 0.4 microM. 24(S), 25-epoxycholesterol was found to be the most potent endogenous agonist (Janowski BA et al. 1999). NR1H3 (LXRα) and NR1H2 (LXRβ) showed similar affinities for these compounds (Janowski BA et al. 1999). In physiological conditions, oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors to alter gene expression and protect the cells from cholesterol overload via: (1) inhibiting intestinal cholesterol absorption; (2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1: (3) activating the conversion of cholesterol to bile acids in the liver; and (4) activating biliary cholesterol and bile acid excretion (reviewed in: 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).

Literature References
PubMed ID Title Journal Year
18063918 Liver X receptors (LXRs). Part I: structure, function, regulation of activity, and role in lipid metabolism

Wójcicka, G, Jamroz-Wiśniewska, A, Horoszewicz, K, Bełtowski, J

Postepy Hig Med Dosw (Online) 2007
22541735 Liver X receptor biology and pharmacology: new pathways, challenges and opportunities

Jakobsson, T, Treuter, E, Gustafsson, JA, Steffensen, KR

Trends Pharmacol. Sci. 2012
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