NR1H2 & NR1H3 regulate gene expression linked to lipogenesis

Stable Identifier
R-HSA-9029558
Type
Pathway
Species
Homo sapiens
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LXRs regulate gene expression linked to lipogenesis
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The liver X receptor α (LXRα or NR1H3) and LXRβ (NR1H2) are nuclear receptors that are activated by endogenous oxidized derivatives of cholesterol known as oxysterols (Janowski BA et al. 1999; Jakobsson T et al. 2012). NR1H2 and NR1H3 act as whole-body cholesterol sensors and their activation results in a net elimination of cholesterol from the body and amelioration of the plasma lipoprotein profile by mobilizing cholesterol from the periphery (Venkateswaran A et al. 2000; Repa JJ et al. 2000a; Ishibashi M et al. 2013). NR1H3 (LXRα) and NR1H2 (LXRβ) also contribute to lowering of whole-body cholesterol levels by shifting acetyl-CoA units from cholesterol de novo biosynthesis to fatty acid synthesis. NR1H2 or 3-induced hepatic lipogenesis in rodents and humans is mediated by direct upregulation of sterol regulatory element-binding protein 1 (SREBF1), the main regulator of hepatic lipogenesis that controls the transcription of genes involved in fatty acid biosynthesis (Schultz JR et al. 2000). NR1H2 & NR1H3 may activate lipogenic gene transcription directly by biding LXR responsive element (LXRE) found in the promoter regions of several genes, such as fatty acid synthase (FAS or FASN) and stearoyl-CoA desaturase 1 (SCD1) (Repa JJ et al. 2000b; Yoshikawa T et al. 2001; Joseph SB et al. 2002; Chu K et al. 2006). Mice carrying a targeted disruption in the NR1H3 (LXRα) gene were deficient in expression of FAS, SCD1, ACC, and SREBF1 (Peet DJ et al. 1998). Mice ablated of both NR1H3 and NR1H2 showed defective hepatic lipid metabolism decreasing lipogenesis by 80% and were resistant to obesity (Repa JJ et al. 2000; Kalaany NY et al. 2005; Beaven SW et al. 2013). Further, the administration of the synthetic NR1H2 or NR1H3 ligands to mice triggered induction of the lipogenic pathway and raised plasma triglyceride levels (Schultz JR et al. 2000). These studies demonstrate the role of NR1H3 (LXRα) and NR1H2 (LXRβ) in the control of lipogenesis.

Literature References
PubMed ID Title Journal Year
17684114 The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor

Herzog, B, Hallberg, M, Seth, A, Woods, A, White, R, Parker, MG

Mol. Endocrinol. 2007
16298468 Liver X receptor preferentially activates de novo lipogenesis in human preadipocytes

Darimont, C, Avanti, O, Zbinden, I, Leone-Vautravers, P, Mansourian, R, Giusti, V, Macé, K

Biochimie 2006
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