RNF186 impairs insulin sensitivity by inducing ER stress in mouse primary hepatocytes.

Abstract RING finger 186 (RNF186) is involved in the process of endoplasmic reticulum (ER)-stress-mediated apoptosis and inflammation of different cell types, such as HeLa cells and colon epithelial cells. However, the physiological and functional roles of RNF186 in peripheral tissues remain largely unknown. In the current study, we investigate the physiological function of RNF186 in the regulation of ER stress with respect to its biological roles in regulating insulin sensitivity in mouse primary hepatocytes. RNF186 expression is induced in the livers of diabetic, obese and diet-induced obese (DIO) mice. Mouse primary hepatocytes were isolated and treated with Ad-RNF186 or Ad-GFP. The results suggest that overexpression of RNF186 increases the protein levels of the ER stress sensors inositol requiring kinase 1 (IRE1) and C/EBP homologous protein (CHOP) protein, as well as the phosphorylation level of eukaryotic initiation factor 2α (eIF2α), in mouse primary hepatocytes. This effect impedes the action of insulin through c-Jun N-terminal kinase (JNK)-mediated phosphorylation of insulin receptor substrate 1 (IRS1). Furthermore, overexpression of RNF186 also significantly increases the levels of proinflammatory cytokines, including TNFα, IL-6 and MCP1. In addition, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, alleviates the expression of ER stress markers induced by RNF186 overexpression. Taken together, the results of the present study show that overexpression of RNF186 induces ER stress and impairs insulin signalling in mouse primary hepatocytes, suggesting that RNF186 merits further investigation as a potential therapeutic target for treatment of insulin-resistance-associated metabolic diseases. [ABSTRACT FROM AUTHOR]