Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

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  • 大植, 隆司
    Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University; Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • 野仲, 葉月
    Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology
  • 西田, 朱里
    Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • 増島, 侑紀
    Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University
  • 高橋, 大輔
    Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University
  • 池田, 貴子
    Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University; Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • 上水, 明治
    Graduate School of Pharmaceutical Sciences, The University of Tokyo
  • 田中, 都
    Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University
  • 国府島, 庸之
    Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
  • 五十嵐, 美樹
    Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology
  • 加藤, 裕教
    Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University; Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University
  • 田中, 智洋
    Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences and Medical School, Nagoya City University
  • 井上, 飛鳥
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • 菅波, 孝祥
    Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University
  • 長谷, 耕二
    Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT)
  • 小川, 佳宏
    Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
  • 青木, 淳賢
    Graduate School of Pharmaceutical Sciences, The University of Tokyo
  • 木村, 郁夫
    Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University; Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University; Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology
  • 大植, 隆司
  • 野仲, 葉月
  • 西田, 朱里
  • 増島, 侑紀
  • 高橋, 大輔
  • 池田, 貴子
  • 上水, 明治
  • 田中, 都
  • 国府島, 庸之
  • 五十嵐, 美樹
  • 加藤, 裕教
  • 田中, 智洋
  • 井上, 飛鳥
  • 菅波, 孝祥
  • 長谷, 耕二
  • 小川, 佳宏
  • 青木, 淳賢
  • 木村, 郁夫

説明

Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.

収録刊行物

  • JCI Insight

    JCI Insight 8 (2), 2023-01-24

    American Society for Clinical Investigation

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