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Research article

Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis

Tzu-Hao Li, Ying-Ying Yang, Chia-Chang Huang, Chih-Wei Liu, Hung-Cheng Tsai, Ming-Wei Lin, Chang-Youh Tsai, Shiang-Fen Huang, Ying-Wen Wang, Tzung-Yan Lee, Yi-Hsiang Huang, Ming-Chih Hou, Han-Chieh Lin
Clinical Science Feb 13, 2019, 133 (3) 531-544; DOI: 10.1042/CS20180873
Tzu-Hao Li
Division of Allergy and Immunology, Taipei Veterans General Hospital, Taipei, TaiwanInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDivision of Allergy and Immunology, Department of Medicine, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan
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Ying-Ying Yang
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, TaiwanDivision of General Medicine, Taipei Veterans General Hospital, Taipei, TaiwanInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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  • http://orcid.org/0000-0003-2919-9853
  • For correspondence: yangyy@vghtpe.gov.twhclin@vghtpe.gov.tw
Chia-Chang Huang
Division of General Medicine, Taipei Veterans General Hospital, Taipei, TaiwanInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Chih-Wei Liu
Division of Allergy and Immunology, Taipei Veterans General Hospital, Taipei, TaiwanInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Hung-Cheng Tsai
Division of Allergy and Immunology, Taipei Veterans General Hospital, Taipei, TaiwanDivision of General Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Ming-Wei Lin
Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Chang-Youh Tsai
Division of Allergy and Immunology, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Shiang-Fen Huang
Division of Infection, Taipei Veterans General Hospital, Taipei, TaiwanInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Ying-Wen Wang
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Tzung-Yan Lee
Department of Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanGraduate Institute of Traditional Chinese Medicine, Chang Guang Menorial Hospital, Linkou, Taiwan
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  • http://orcid.org/0000-0003-4097-2085
Yi-Hsiang Huang
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Ming-Chih Hou
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Han-Chieh Lin
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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  • For correspondence: yangyy@vghtpe.gov.twhclin@vghtpe.gov.tw
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Abstract

Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

  • alcohol steatohepatitis
  • adipose tissue dysfunction
  • autophagy dysfunction
  • peroxisome proliferator-activated receptor
  • Abbreviations

    ALD,
    alcoholic liver disease;
    ALT,
    Alanine transaminase;
    ASH,
    alcohol steatohepatitis;
    AT,
    adipose tissue;
    EtOH,
    ethanol;
    FA,
    fatty acid;
    FFA,
    free FA;
    IL-1β,
    interleukin-1β;
    LC3-II,
    light chain 3 -II;
    MCP,
    monocyte chemoattractant protein;
    PCNA,
    proliferating cell nuclear antigen;
    PE,
    Phycoerythrin;
    PH,
    primary hepatocyte;
    PPAR,
    peroxisome proliferator-activated receptor;
    TG,
    triglyceride;
    ZO-1,
    Zonula occludens-1;
    3-MA,
    3-methyladenine
    • © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
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    February 2019

    Volume: 133 Issue: 3

    Clinical Science: 133 (3)
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    Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis
    Tzu-Hao Li, Ying-Ying Yang, Chia-Chang Huang, Chih-Wei Liu, Hung-Cheng Tsai, Ming-Wei Lin, Chang-Youh Tsai, Shiang-Fen Huang, Ying-Wen Wang, Tzung-Yan Lee, Yi-Hsiang Huang, Ming-Chih Hou, Han-Chieh Lin
    Clinical Science Feb 2019, 133 (3) 531-544; DOI: 10.1042/CS20180873
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    Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis
    Tzu-Hao Li, Ying-Ying Yang, Chia-Chang Huang, Chih-Wei Liu, Hung-Cheng Tsai, Ming-Wei Lin, Chang-Youh Tsai, Shiang-Fen Huang, Ying-Wen Wang, Tzung-Yan Lee, Yi-Hsiang Huang, Ming-Chih Hou, Han-Chieh Lin
    Clinical Science Feb 2019, 133 (3) 531-544; DOI: 10.1042/CS20180873

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    Keywords

    alcohol steatohepatitis
    adipose tissue dysfunction
    autophagy dysfunction
    peroxisome proliferator-activated receptor

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