Elsevier

Journal of Hepatology

Volume 60, Issue 4, April 2014, Pages 847-854
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2013.12.003Get rights and content

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.

Introduction

Non-alcoholic fatty liver disease (NAFLD), characterized by aberrant triglyceride accumulation in the liver has become one of the most common liver diseases all over the world and affects up to one-third of adults in developed countries [1]. Growing evidence suggests that NAFLD prevalence is markedly increased in aging humans [2], [3]. The prevalence of NAFLD in population aged above 60 years was twice more than those between 20 and 40 years [4]. One study compared the age in subjects with or without NAFLD and showed that the average age was higher in individuals with hepatic steatosis than in those without [5]. However, the molecular mechanism underlying the initiation and progression of NAFLD in elderly people still remains unknown.

The imbalance between triglyceride synthesis and clearance results in triglyceride accumulation in the liver. Hepatic lipogenesis is mainly regulated by SREBP-1c, which increases the expression of genes involved in de novo lipogenesis such as Fasn, SCD-1, and Acly [6]. Increased expression of SREBP-1c has been implicated in many cases of hepatic steatosis [7], [8]. Moreover, SREBP-1c expression was tightly regulated by many nuclear receptors, including Liver X receptor (LXR) and farnesoid X receptor (FXR), which regulate SREBP-1c in an opposite direction, respectively [9], [10].

Initially, FXR was considered a central regulator of bile acid homeostasis [11], [12], [13]. Subsequent studies demonstrated that FXR also played a crucial role in the regulation of hepatic triglyceride metabolism [9]. Mice with FXR deficiency exhibited hepatic steatosis and hyperlipidemia, whereas overexpression or activation of FXR could efficiently improve hepatic triglyceride accumulation and hyperlipidemia in obese rodents [14], [15], [16]. Consistently, our previous study revealed that FXR heterozygous mice also displayed fatty liver under a short-term high-fat-diet feeding [17]. In addition, hepatic FXR expression was markedly reduced in obese rodents and NAFLD patients, suggesting that FXR dysfunction might play a causal role in the development of hepatosteatosis in obesity [17], [18].

In the present study, we speculate that FXR dysfunction might be involved in the development of hepatosteatosis in aging mice. Our study provides a novel insight for the mechanism of aging-induced fatty liver and proposed a promising therapeutic target for the related diseases.

Section snippets

Animal treatment

C57BL/6 mice were purchased from the Shanghai Laboratory Animal Company (SLAC, Shanghai, China). JNK1 knockout mice were obtained from Jackson Laboratories Bar (Harbor, Maine, USA). All mice were maintained in a temperature and light-controlled environment. Mice were housed in ventilated microisolator cages under a 12-h light and dark cycle with free access to food and water, and fasted overnight before they were sacrificed. GW4064, thapsigargin, tunicamycin, tauroursodeoxycholate (TUDCA) and

Increased hepatic triglyceride content in aging mice

To determine the hepatic triglyceride (TG) accumulation in aging mice, we measured TG contents in C57BL/6 male mice aged 2 months (young), 8 months (middle) and 18 months (old). We and others have shown that expression of FXR was reduced in obese animals and humans [17], [18], [19]. Therefore, to exclude the potential effect of obesity on hepatic lipid deposition, we chose body weight comparable mice (Fig. 1A). Blood glucose and cholesterol levels were not significantly different among the three

Discussion

In the present study, we found that hepatic TG was markedly accumulated in aging mice with body weight comparable. At molecular levels, we found that lipogenic genes were up-regulated, which is consistent with previous reports [31], [32]. Some studies showed that PPARα expression was reduced in aging mice, while some other studies including ours could not detect this change [32], [33]. The reason for this inconsistence remains unknown and may be relevant to the different animal models and

Financial support

This study was supported by the grants from National Key Basic Research Program of China (973 Program, 2012CB524902), China Natural Science Foundation (No. 81070681, 81100616, 81200636, 81000320, 81370959).

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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    These authors contributed equally to this work.

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