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

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

Author information

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.

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

PMID:
24333182
DOI:
10.1016/j.jhep.2013.12.003
[Indexed for MEDLINE]
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