JCI Insight (Jan 2023)

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

  • Ryuji Ohue-Kitano,
  • Hazuki Nonaka,
  • Akari Nishida,
  • Yuki Masujima,
  • Daisuke Takahashi,
  • Takako Ikeda,
  • Akiharu Uwamizu,
  • Miyako Tanaka,
  • Motoyuki Kohjima,
  • Miki Igarashi,
  • Hironori Katoh,
  • Tomohiro Tanaka,
  • Asuka Inoue,
  • Takayoshi Suganami,
  • Koji Hase,
  • Yoshihiro Ogawa,
  • Junken Aoki,
  • Ikuo Kimura

Journal volume & issue
Vol. 8, no. 2

Abstract

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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.

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