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

  • Author Footnotes
    † These authors contributed equally to this work.
    Xuelian Xiong
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    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
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  • Author Footnotes
    † These authors contributed equally to this work.
    Xiaolin Wang
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    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
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  • Author Footnotes
    † These authors contributed equally to this work.
    Yan Lu
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    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
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  • E. Wang
    Affiliations
    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
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  • Zhijian Zhang
    Affiliations
    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
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  • Jian Yang
    Affiliations
    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
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  • Huijie Zhang
    Affiliations
    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
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  • Xiaoying Li
    Correspondence
    Corresponding author. Address: Shanghai Institute of Endocrinology and Metabolism, 197 Ruijin 2nd Road, Shanghai 200025, China. Tel./fax: +86 21 54660108.
    Affiliations
    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
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  • Author Footnotes
    † These authors contributed equally to this work.
Published:December 11, 2013DOI:https://doi.org/10.1016/j.jhep.2013.12.003

      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.

      Abbreviations:

      NAFLD (Non-alcoholic fatty liver disease), TG (triglyceride), ER (endoplasmic reticulum), THA (thapsigargin), Tun (tunicamycin), TUDCA (tauroursodeoxycholate), MPH (mouse primary hepatocyte), FXR (farnesoid X receptor), HNF1α (hepatocyte nuclear factor 1 alpha), SREBP-1c (sterol regulatory element binding transcription factor 1c), FASN (fatty acid synthase), SCD-1 (stearoyl-Coenzyme A desaturase 1), Acly (Acetyl-CoA ylase), LXR (liver X receptor), PPARα (peroxisome proliferative activated receptor), CPT-Iα (carnitine palmitoyltransferase 1α), MCAD (medium-chain specific acyl-CoA dehydrogenase), ACOX1 (acyl-coenzyme A oxidase 1), LRH-1 (liver receptor homolog-1), SHP (small heterodimer partner), BSEP (bile salt export pump), PERK (pancreatic eIF-2alpha kinase), Grp78 (78kDa glucose-regulated protein), ATF6 (activating transcription factor 6), JNK (c-Jun amino-terminal kinase), IRE1 (inositol-requiring enzyme-1), XBP1 (X-box-binding protein 1)

      Keywords

      Linked Article

      • Failing FXR expression in the liver links aging to hepatic steatosis
        Journal of HepatologyVol. 60Issue 4
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          Aging is characterized, amongst other ailments, by an increased prevalence of symptoms of the metabolic syndrome such as elevated blood pressure, dyslipidemia and insulin resistance, which rise from 7% in the 20–29 year-old population to 44% in the 60–69 year-old population [1]. Excessive accumulation of fat in the liver, or steatosis, is a predictor of these metabolic alterations and is as such often considered as the hepatic manifestation of the metabolic syndrome. Ectopic fat accumulation as well as inappropriate lipid partitioning in the liver is believed to play a driving role in the etiology of insulin resistance [2] and considered by many as the primary step in the development of non-alcoholic fatty liver disease (NAFLD).
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