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Title: Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - 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{sup −/−}) 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{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/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 concentrationsmore » of hepatic bile acids in FXR{sup −/−}/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{sup −/−}/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.« less
Authors:
; ;  [1] ;  [2] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1]
  1. Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)
  2. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China)
Publication Date:
OSTI Identifier:
22416437
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 448; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; BILE ACIDS; CARBOXYLASE; CARNITINE; CHOLESTEROL; COENZYMES; GTP-ASES; HISTOLOGY; HORMONES; HYDROXYLASES; LIPASES; LIPOPROTEINS; LIVER; METHIONINE; MICE; MONOCYTES; OXIDASES; PATHOGENESIS; RECEPTORS; TRIGLYCERIDES