Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride (TG) contents. The prevalence of NAFLD is increased with aging. However, the molecular mechanism for aging-induced fatty liver remains poorly understood. Methods: Hepatic TG contents and gene expression profiles were analyzed in body weight-matched young (2 months), middle (8 months) and old (18 months) C57BL/6 mice. Endoplasmic reticulum (ER) stress and farnesoid X receptor (FXR) expression were examined. The mechanism of ER stress activation in the regulation of FXR expression was further investigated. Results: In the present study, we found that TG was markedly accumulated and lipogenic genes were up-regulated in the liver of C57BL/6 mice aged 18 months. FXR, a key regulator of hepatic lipid metabolism was down-regulated in these old mice. At molecular levels, ER stress was activated in old mice and repressed FXR expression through inhibition of hepatocyte nuclear factor 1 alpha (HNF1 alpha) transcriptional activity. Conclusions: Our findings demonstrate that FXR down-regulation plays a critical role in aging-induced fatty liver. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.