NR1H2 or NR1H3, NRIP1 bind the SCD gene

Stable Identifier
Reaction [binding]
Homo sapiens
LXR, NRIP1 bind the SCD gene
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Stearoyl-CoA desaturase (SCD) is an enzyme required for the biosynthesis of oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides and cholesterol esters (Bene H et al. 2001; Paton CM & Ntambi JM 2009). Liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) are the oxysterol receptors that were shown to regulate the expression of SCD gene in mouse liver, mouse J774 macrophages cells, human hepatoma HuH7 and human arterial endothelial cells (HAEC) (Wang Y et al. 2004; Chu K et al. 2006; Herzog B et al. 2007; Peter A et al. 2008). The evidence for the Reactome event of NR1H2,3- mediated SCD activity comes mostly from the studies with the synthetic NR1H2,3 agonist T0901317 (Chu K et al. 2006; Peter A et al. 2008). Serial deletion and point mutation analyses in reporter gene assays identified an NR1H2,3 (LXR) response element in the mouse SCD1 promoter (Chu K et al. 2006). Further, a gel mobility shift assay showed the binding of NR1H3 (LXRα):RXRA heterodimer to the LXRE-DR4 element in the promoter region of the mouse SCD1 gene (Chu K et al. 2006). The human SCD promoter structure is very similar to that of the mouse SCD1 isoform and contains conserved regulatory sequences for the binding of several transcription factors (Bene H et al. 2001). Analysis of hepatic lipogenic gene expression indicated that nuclear receptor-interacting protein 140 (RIP140 or NRIP1) was required for NR1H3 to be able to stimulate the expression of the SCD gene in WT and NRIP1 null mice after administration of T0901317 (Herzog B et al. 2007). These findings are supported by the failure of T0901317 to stimulate the expression of SCD gene in cultured human hepatoma HuH7 cells depleted of NRIP1 by siNRIP1 (Herzog B et al. 2007). Further, chromatin immunoprecipitation (ChIP) assays using HuH7 cells treated with T0901317 showed that both NR1H3 (LXRα) and NRIP1 bind directly to promoters in the vicinity of the LXRE of the NR1H2,3 target genes FAS, SREBP1c and NR1H3 (Herzog B et al. 2007). Thus, NRIP1 functions as a coactivator of NR1H2,3 and is required to stimulate expression of genes involved in lipogenesis including SCD gene. However, the function of NRIP1 as a cofactor for NR1H2,3 in liver varies according to the target genes and metabolic process, serving as a coactivator in lipogenesis but as a corepressor in gluconeogenesis (Herzog B et al. 2007). Studies performed with T0901317 in wildtype vs. NR1H3-/- (LXRα-/-) and NR1H2 (LXRβ -/-) mice suggest that SCD1 is primarily regulated by NR1H3 (Zhang X et al. 2014).

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