Expression of SCD regulated by NR1H2 or NR1H3

Stable Identifier
R-HSA-9605060
Type
Reaction [omitted]
Species
Homo sapiens
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The stearoyl CoA desaturase (SCD) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SCD is an endoplasmic reticulum (ER) enzyme that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids that are either synthesized de novo or derived from the diet (Bene H et al. 2001; Paton CM & Ntambi JM 2009). Liver X receptors (LXRα/NR1H3 or LXRβ/NR1H2) are oxysterol receptors that regulate the gene expression of SCD. The evidence for the Reactome event of the induction of SCD gene expression by NR1H3 or NR1H2 comes from the studies with T0901317, the synthetic NR1H2,3 agonist, that has been shown to increase SCD gene expression in mouse liver and human arterial endothelial cells (HAEC) by 10- and 3-fold, respectively (Chu K et al. 2006; Peter A et al. 2008). Treatment with 22(R)-hydroxycholesterol, a natural ligand of NR1H2,3, increased the SCD activity in mouse macrophages J774 and thus supported the ability of NR1H2,3 to regulate SCD (Wang Y et al. 2004). NR1H2,3 has been presumed to regulate SCD protein level through the activation of sterol regulatory element-binding protein (SREBP1) and its consequent binding to SREBP1 binding site (SRE) (Schultz JR et al. 2000; Zhang X et al. 2014). However, studies with SREBP1c -/- mice have suggested that NR1H2,3 upregulate SCD in an SREBP1c-independent manner (Chu K et al. 2006). In HAEC cells, the NR1H2,3 activation increased SCD mRNA and protein expression, which served to protect the cells from saturated fatty acid-induced lipotoxicity, apoptosis and IL-6 and IL-8 expression (Peter A et al. 2008). Analysis of hepatic lipogenic gene expression indicated that nuclear receptor-interacting protein 140 (RIP140 or NRIP1) was required for the ability of NR1H3 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). 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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