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

Xuelian Xiong; Xiaolin Wang; Yan Lu; E Wang; Zhijian Zhang; Jian Yang; Huijie Zhang; Xiaoying Li

doi:10.1016/j.jhep.2013.12.003

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

J Hepatol. 2014 Apr;60(4):847-54. doi: 10.1016/j.jhep.2013.12.003. Epub 2013 Dec 11.

Authors

Xuelian Xiong¹, Xiaolin Wang¹, Yan Lu¹, E Wang¹, Zhijian Zhang¹, Jian Yang¹, Huijie Zhang¹, Xiaoying Li²

Affiliations

¹ Shanghai Institute of Endocrinology and Metabolism, Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Shanghai Institute of Endocrinology and Metabolism, Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; The Key Laboratory of Endocrine Tumors and the Division of Endocrine and Metabolic Diseases, E-Institute of Shanghai Universities, Shanghai 200025, China; Chinese-French Laboratory of Genomics and Life Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: lixy@sibs.ac.cn.

PMID: 24333182
DOI: 10.1016/j.jhep.2013.12.003

Abstract

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 (HNF1α) transcriptional activity.

Conclusions: Our findings demonstrate that FXR down-regulation plays a critical role in aging-induced fatty liver.

Keywords: Aging; Endoplasmic reticulum stress; Farnesoid X receptor; Non-alcoholic fatty liver disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Aging / metabolism*
Animals
Down-Regulation
Endoplasmic Reticulum Stress*
Female
Hepatocyte Nuclear Factor 1-alpha / genetics
Hepatocyte Nuclear Factor 1-alpha / metabolism
Lipogenesis / genetics
Liver / metabolism
Liver / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Non-alcoholic Fatty Liver Disease / etiology*
Non-alcoholic Fatty Liver Disease / genetics
Non-alcoholic Fatty Liver Disease / metabolism*
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Transcriptome
Triglycerides / metabolism

Substances

Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Receptors, Cytoplasmic and Nuclear
Triglycerides
farnesoid X-activated receptor