Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84
Ryuji Ohue-Kitano, … , Junken Aoki, Ikuo Kimura
Ryuji Ohue-Kitano, … , Junken Aoki, Ikuo Kimura
Published December 8, 2022
Citation Information: JCI Insight. 2023;8(2):e165469. https://doi.org/10.1172/jci.insight.165469.
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Research Article Hepatology Inflammation

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

Abstract

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.

Authors

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

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Figure 6

GPR84 activation improves NASH.

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GPR84 activation improves NASH. (A) GPR84 expression in human liver (con...
(A) GPR84 expression in human liver (control, n = 5; NAFL, n = 9; NASH, n = 39). Pearson’s correlation coefficient between the expression levels of GPR84 and TNF or TGFB1 (n = 53). (B) Ligand affinity of embelin for GPR84 using Tet-On/Off (n = 6 independent cultures with Dox, from 2 biological replicates; n = 6 independent cultures without Dox, from 2 biological replicates) and TGF-α shedding assay (n = 6 independent cultures with GPR84-encoding plasmid; n = 6 independent cultures with mock). AP-TGFα, alkaline phosphatase-tagged TGF-α. (C) Antiinflammatory effect of embelin-stimulated GPR84. RAW264.7 cells and RAW-KO cells were pretreated with palmitic acid (C16:0; 200 μM) and followed by stimulation of embelin for 3 hours (n = 6 per group; independent experiments). Data are represented as relative to the gene expression in untreated cells. (D) Improvement of inflammation and fibrosis in the livers of mice fed CDAHFD for 10 weeks. Expression of inflammation- and fibrosis-related genes in the liver (WT, n = 8 tissues; Gpr84–/–, n = 4 tissues per group per group). Data are represented as relative to the gene expression in control mice (untreated with embelin). (E) Suppression of inflammation and fibrosis in CCl4-accelerated NASH. Expression of inflammation- and fibrosis-related genes in the liver (WT, n = 8; Gpr84–/–, n = 4 tissues per group). Data are represented as relative to the gene expression in control mice (untreated with embelin). (F) NAS after administration of the GPR84 agonist embelin. *P < 0.05; **P < 0.01 (Kruskal-Wallis with Dunn’s post hoc test: C; Mann-Whitney U test: D–F [CCl4]; Student’s t test: F [CDAHFD]). All data are presented as the mean ± SEM.