IDH2 protects against nonalcoholic steatohepatitis by alleviating dyslipidemia regulated by oxidative stress.

Nonalcoholic fatty liver disease (NAFLD) has become an epidemic across the world. A large and growing unmet therapeutic requirement has inspired plenty exploration in the field. Isocitrate dehydrogenase 2 (IDH2), localized in mitochondria, decreases NADP+ to NADPH during the decarboxylation of isocitrate to α-ketoglutarate. Although the NADPH producing system is closely related to oxidative stress and lipid accumulation, the effects of IDH2 on hepatic steatosis and the associated metabolic disorders remain elusive. In our study, we found that IDH2 expression was markedly reduced by palmitate stimulation in primary hepatocytes, accompanied with increased lipid accumulation. In response to high fat diet (HFD) administration, IDH2 knockout (KO) further contributed to the pathological progression of insulin resistance and hepatic steatosis. In addition, HFD treatment-induced mitochondrial oxidative injury and dyslipidemia were markedly elevated in liver of mice with IDH2 knockout. The expression of mitochondrial fission and fusion mediators, including dynamin-related protein 1 (DRP1), mitofusin 1 (MFN1) and fission protein 1 (FIS1), induced by HFD was further exacerbated in liver of IDH2 knockout mice. Furthermore, the over-expression of IDH2 in hepatocytes led to the suppression of ROS production and DRP1 expression, but the alleviation of dyslipidemia. Taken together, these results established IDH2 as a critical suppressor of steatohepatitis, which might be a promising therapeutic target for developing effective treatment to prevent nonalcoholic steatohepatitis progression.