Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38–45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress.
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.
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