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 - 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.
UR - https://www.scopus.com/pages/publications/85147047496
UR - https://www.scopus.com/pages/publications/85147047496#tab=citedBy
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 -