Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance.
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.
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Yanyan
Y
Qiu
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Xianxian
X
Sui
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Yongkun
Y
Zhan
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
Chen
C
Xu
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Xiaobo
X
Li
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Yanxia
Y
Ning
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Laboratory of Medical Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: zhixiuling@fudan.edu.cn.
Xiuling
X
Zhi
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: hyin@shmu.edu.cn.
Lianhua
L
Yin
D000818:Animals; D004075:Diglycerides / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
D004075:Diglycerides; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein
Farnesoid x receptor; Fatty liver; Insulin resistance; Steroidogenic acute regulatory protein