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. 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, GPR84deficient mice exhibited non-alcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage over-activation. 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. Exogenous GPR84 stimulation is therefore a potential strategy for treating NASH.

The GPR84 molecule is a mediator of a subpopulation of retinal microglia that promote TNF/IL‐1α expression via the rho‐ROCK pathway after optic nerve injury

“…Thy1‐EGFP mice were kindly provided by Dr. Kenji Kashiwagi (Yamanashi University, Japan) and Iba1‐EGFP mice were kindly provided by Prof. Shinichi Kohsaka (National Institute of Neuroscience, Japan) (Ito, 1998). A previously established line of GPR84‐deficient mice (Nonaka et al, 2022; Ohue‐kitano et al, 2022) was kindly provided by Prof. Ikuo Kimura (Kyoto University, Japan). Except where noted, 8‐ to 16‐week‐old mice were used in the experiments.…”

“…Thy1-EGFP mice were kindly provided by Dr. Kenji Kashiwagi (Yamanashi University, Japan) and Iba1-EGFP mice were kindly provided by Prof. Shinichi Kohsaka (National Institute of Neuroscience, Japan) (Ito, 1998). A previously established line of GPR84-deficient mice (Nonaka et al, 2022;Ohue-kitano et al, 2022)…”

Regulation of the pro‐inflammatory G protein‐coupled receptor GPR84

“…GPR84 is a rhodopsin‐like class A GPCR (Marsango et al, 2020). Despite the receptor being able to bind and respond to medium chain fatty acids (MCFA), particularly, decanoic acid (C10), undecanoic acid (C11) and dodecanoic acid (C12), and also a series of hydroxylated MCFA (Kaspersen et al, 2017; Ohue‐Kitano et al, 2023; Suzuki et al, 2013; Wang et al, 2006) GPR84 is still described as a ‘Class A orphan’ receptor (Luscombe et al, 2020; Marsango et al, 2020). This is because the potency of MCFAs in activating the receptor is modest (Nikaido et al, 2015; Recio et al, 2018; Southern et al, 2013; Suzuki et al, 2013; Wang et al, 2006), and there is limited evidence to suggest the involvement of GPR84 in the physiological function of MCFAs.…”

Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists

“…3-(2-(4-Chloro-2-cyclohexylphenoxy)ethyl)pyridine 1-oxide (27). Following general procedure B, 27 was obtained from 27a (100 mg, 0.317 mmol).…”

“…GPR84 mRNA expression in leukocytes and adipocytes can be significantly upregulated by vitamin D and inflammatory stimuli like lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα), as well as chronic low-grade inflammation . Activation of GPR84 by synthetic agonists in vitro results in enhanced phago­cytosis, immune cell migration, and increased secretion of cytokines, chemokines, and other inflammatory mediators. ,,, GPR84 agonists have been shown to mediate enhanced phago­cytosis of adipocyte plasma membrane-associated protein (APMAP)-deficient cancer cells, suppress lipotoxicity-induced macrophage over-activation, trigger increased bacterial adhesion, show anti-atherosclerotic effects, and play a role in the regulation of mitochondrial metabolism, suggesting that the activation of GPR84 may be beneficial for cancer, bacteria killing, and metabolic dysfunction. ,− …”