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, GPR84-deficient 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 prevented NASH in mouse models. Exogenous GPR84 stimulation is therefore a breakthrough strategy for treating NASH.

RNA was extracted from the liver and bone marrow from NC-fed and HFD-fed mice using an RNeasy mini kit (Qiagen) and RNAiso Plus reagent (TAKARA). Liver and bone marrow were obtained from WT mice and Gpr84-deficient mice. The RNA sequencing libraries were generated with the TruSeq RNA Library Prep Kit (Illumina) and sequenced on an Illumina platform. Approximately 4Gb paired-end reads of length 100 bp per sample were obtained. The RNA sequencing data were pre-processed using Trimmomatic. The quality of RNA was assessed using FastQC.