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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 4

GPR84 suppresses BM-derived hepatic macrophages.

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GPR84 suppresses BM-derived hepatic macrophages.
(A) Expression of Gpr84...
(A) Expression of Gpr84 in the liver after HFD feeding for 5 weeks (n = 7 tissues per group). Data are represented as relative to the gene expression in before HFD-fed mice. (B) Gpr84 expression in BM-derived monocytes, hepatic macrophages, Kupffer cells, hepatic stellate cells, and hepatocytes isolated from WT mice fed NC for 12 weeks (n = 5–6 per group). Data are represented as relative to the gene expression in macrophage. (C) Change of Gpr84 expression after HFD feeding (NC- vs. HFD-fed group, n = 5–6 per group). Data are represented as relative to the gene expression in NC-fed mice. (D) Flow cytometric analysis of BM-derived hepatic macrophage population and Tnf expression in WT and Gpr84–/– mice fed the HFD for 12 weeks (n = 4 per group). BM-derived hepatic macrophages, CD45+Ly6C+F4/80+CD11bhiCX3CR1+. (E) Flow cytometric analysis showing hepatic cell profile in BM-chimeric mice fed the HFD for 8 weeks (n = 8–9 per group) and NAS (n = 4 per group). WT recipient mice (CD45.1) after BM transplantation from WT or Gpr84–/– donor mice (CD45.2). (F) Antiinflammatory effect of MCFA-stimulated GPR84 (n = 8 per group; independent experiments). Data are represented as relative to the gene expression in untreated cells. (G) Intracellular MCFA production in AML12 cells (mouse hepatocyte cell line) treated with palmitic acid for 48 hours (n = 8 per group; independent experiments). (H) Tnf expression in RAW264.7 cells cocultured with AML12 prestimulated by palmitic acid (C16:0; n = 6 per group; independent experiments). *P < 0.05; **P < 0.01 (Mann-Whitney U test: A and C–E upper, G; Student’s t test: E lower; and Kruskal-Wallis with Dunn’s post hoc test: F and H). All data are presented as the mean ± SEM.

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