TY - JOUR
T1 - Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84
AU - Ohue-Kitano, Ryuji
AU - Nonaka, Hazuki
AU - Nishida, Akari
AU - Masujima, Yuki
AU - Takahashi, Daisuke
AU - Ikeda, Takako
AU - Uwamizu, Akiharu
AU - Tanaka, Miyako
AU - Kohjima, Motoyuki
AU - Igarashi, Miki
AU - Katoh, Hironori
AU - Tanaka, Tomohiro
AU - Inoue, Asuka
AU - Suganami, Takayoshi
AU - Hase, Koji
AU - Ogawa, Yoshihiro
AU - Aoki, Junken
AU - Kimura, Ikuo
N1 - Funding Information:
This work was partly supported by research grant JP21gm1010007 from the Japan Agency for Medical Research and Development (to IK), Japan Society for the Promotion of Science KAKENHI grant JP21H04862 (to IK), Japan Science and Technology Agency OPERA grant JPMJOP1833 (to IK), and Japan Science and Technology Agency Moonshot R&D grant JPMJMS2023 (to IK). Support was also received from the Smoking Research Foundation (to IK) and the Nisshin OilliO Group (to IK).
Publisher Copyright:
© 2023, Ohue-Kitano et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2023/1/24
Y1 - 2023/1/24
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.165469
DO - 10.1172/jci.insight.165469
M3 - Article
C2 - 36480287
AN - SCOPUS:85147047496
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 2
M1 - e165469
ER -