Deletion of retinoic acid-related orphan receptor gamma reduces body weight and hepatic lipids in mice by modulating the expression of lipid metabolism genes

Abstract

How to cite this article: Iqbal J, Jahangir Z, Veluru D, Otaibi AA, Mubarak SA, Subie BA, Alghanem AF, Qarni AA, Bakillah A, Hawwari A. Deletion of retinoic acid-related orphan receptor gamma reduces body weight and hepatic lipids in mice by modulating the expression of lipid metabolism genes. Vessel Plus 2019;3:40. http://dx. AbstractAim: Retinoic acid-related orphan receptor γ (RORγ) functions as a ligand-dependent transcription factor and its loss has been shown to affect the circadian expression of lipid metabolism genes. However, its effect on body weight gain and hepatic lipids is not well understood. In this study, we investigated the impact of Rorγ gene deletion on changes in body weight and hepatic lipids.Methods: Body weight and lipids were analyzed in the plasma and liver. Expression of lipid metabolism genes in the liver was evaluated in wild type and Rorγ knockout mice. Results:We show that deletion of RORγ results in reduced body weight and fewer lipids in the liver. Analysis of gene expression showed that deletion of Rorγ resulted in an overall lower expression of genes and transcription factors involved in lipid biosynthesis. We observed a decrease in the gene expression of cholesterol biosynthesis, efflux, and esterification but an increase in bile acid synthesis. There was a decrease in fatty acid and triglycerides biosynthesis genes and an increase in the fatty acid uptake genes. The decrease in the expression of lipid biosynthesis genes was accompanied by the decrease in the sterol response element binding protein (Srebp) genes. We observed an increase in the expression of peroxisome proliferator-activated receptor alpha (Ppara) and a decrease in the expression of acetyl-CoA carboxylase 2 (Acc2 ) genes. Conclusion:Our data suggest that RORγ regulates body weight and lipid metabolism genes and its modulation may be beneficial for the management of obesity and related lipid metabolic disorders.

Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6

“…The case of CD36 illustrates context-dependent regulation given that this gene is activated in the liver (Zhou et al 2020), but repressed in skeletal muscle by Nr2f6 in mice and humans. This finding suggests that Nr2f6 may be bound to DNA but kept in a repressive state by posttranslational modifications or interaction partners, such as RAR Related Orphan Receptor γ (RORγ), another regulator of CD36 transcription in muscle (Raichur et al 2007) and liver (Iqbal et al 2019). In Th17 lymphocytes, Nr2f6 can compete with RORγ for binding at the IL17 promoter, maintaining the repressive state.…”