title: Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis.
abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR(-/-)) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR(-/-) mice fed MCD diet (FXR(-/-)/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR(-/-)/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR(-/-)/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR(-/-)/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xijun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Xue
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032, China.
authors.forename: Xizhong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: shechen@fudan.edu.cn.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: zhangsi@fudan.edu.cn.
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000209:etiology; D002796:Choline Deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D008715:Methionine; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: FXR; Fibrosis; Hepatic steatosis; Inflammation; NFALD