Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2017-04, Vol.1863 (4), p.978-990
• Main Authors: Qiu, Yanyan, Sui, Xianxian, Zhan, Yongkun, Xu, Chen, Li, Xiaobo, Ning, Yanxia, Zhi, Xiuling, Yin, Lianhua
• Format: Article
• Language: English
• Subjects: Animals; Diglycerides - genetics; Diglycerides - metabolism; Farnesoid x receptor; Fatty liver; Female; Gene Expression Regulation; Humans; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - therapy; Phosphoproteins - genetics; Phosphoproteins - metabolism; Steroidogenic acute regulatory protein
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2017.01.026

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR). StAR expression was also examined in pathology samples of patients with fatty liver by immunohistochemical staining. We found that the expression level of StAR was reduced in the livers obtained from fatty liver patients and NAFLD mice. Additionally, StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis due to the activation of farnesoid x receptor (FXR). StAR overexpression attenuated the impairment of insulin signaling in fatty liver. This protective role of StAR was owing to a reduction of intracellular diacylglycerol levels and the phosphorylation of PKCε. Furthermore, FXR inactivation reversed the observed beneficial effects of StAR. The present study revealed that StAR overexpression can reduce hepatic lipid accumulation, regulate glucose metabolism and attenuate insulin resistance through a mechanism involving the activation of FXR. Our study suggests that StAR may be a potential therapeutic target for NAFLD. [Display omitted] •StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis.•StAR overexpression attenuated the impairment of insulin signaling in fatty liver.•StAR overexpression reduced the level of diacylglycerol and the phosphorylation of PKCε.•This protective role of StAR was owing to the activation of FXR.