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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

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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 1

GPR84 deficiency accelerates HFD-induced chronic inflammation.

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GPR84 deficiency accelerates HFD-induced chronic inflammation.
(A) TNF-α...
(A) TNF-α levels (NC-fed group, n = 5; HFD-fed group, n = 6–7). NC, normal chow. (B) Expression of Tnf in liver, Epi, muscle, small intestine, and colon (n = 4 independent experiments). Data are represented as relative to the gene expression in WT mice. Epi, epididymal white adipose tissue. (C) RNA-Seq transcriptome profiling in liver in WT and Gpr84–/– mice fed the HFD for 5 weeks. Heatmap shows results of 2-dimensional hierarchical clustering of 59 genes related to inflammation (n = 5 per group). (D) Expression of fibrosis-related genes — Col1a (left), Tgfb1 (middle), and Acta2 (right) — in the liver (n = 8–9). Data are represented as relative to the gene expression in WT mice. *P < 0.05; **P < 0.01 (Mann-Whitney U test: A, B, and D). All data are presented as the mean ± SEM.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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