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

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.

Automated summary

Medium-chain triglycerides (MCTs) are unique forms of dietary fat that have various health benefits. A receptor called G protein-coupled 84 (GPR84) acts as a receptor for medium-chain fatty acids (MCFAs), but its role in nutritional signaling is still unclear. This study found that GPR84 plays a protective role in hepatic functions by sensing increases in MCFAs and suppressing lipotoxicity-induced macrophage overactivation. Additionally, stimulating GPR84 or administering MCTs or MCFAs improved nonalcoholic steatohepatitis (NASH) in mouse models, suggesting a potential strategy for treating NASH.