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Updated: Aug 18, 2025
A Model of Experimental Steatosis In Vitro: Hepatocyte Cell Culture in Lipid Overload-Conditioned Medium
Published on: May 18, 2021
Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84
Ryuji Ohue-Kitano1,2, Hazuki Nonaka3, Akari Nishida2
1Laboratory of Molecular Neurobiology, Graduate School of Biostudies and.
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.
Insights
Medium-chain fatty acids (MCFAs) signal through G protein-coupled 84 (GPR84) to protect the liver from high-fat diet damage. Stimulating GPR84 with MCFAs or agonists can treat nonalcoholic steatohepatitis (NASH).
Area of Science:
- Biochemistry
- Immunology
- Hepatology
Background:
- Medium-chain triglycerides (MCTs) are dietary fats composed of medium-chain fatty acids (MCFAs).
- G protein-coupled 84 (GPR84) is an orphan receptor that binds MCFAs, but its role in nutritional signaling is unclear.
- Diet-induced liver conditions like nonalcoholic steatohepatitis (NASH) pose significant health challenges.
Purpose of the Study:
- To investigate the role of endogenous and dietary MCFAs signaling via GPR84 in liver function.
- To determine if GPR84 activation can protect against diet-induced liver lipotoxicity and NASH progression.
- To explore GPR84 agonists and specific MCFAs as potential therapeutic strategies for NASH.
Main Methods:
- Utilized GPR84-deficient mice fed a high-fat diet (HFD) to assess hepatic function and fibrosis.
- Measured hepatic MCFA levels and macrophage activation under HFD conditions.
- Administered MCTs, specific MCFAs (C10:0, C12:0, C8:0), and GPR84 agonists to mouse models of NASH.
Main Results:
- GPR84-deficient mice on HFD developed nonalcoholic steatohepatitis (NASH) and hepatic fibrosis, but not steatosis.
- Under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation, correlating with increased hepatic MCFA levels.
- Administration of MCTs, C10:0 or C12:0 MCFAs, or GPR84 agonists ameliorated NASH in mouse models.
Conclusions:
- Endogenous MCFA-mediated GPR84 signaling protects hepatic functions from diet-induced lipotoxicity.
- GPR84 acts as an immunomodulating receptor sensing increased MCFAs to mitigate excessive dietary fat toxicity.
- Exogenous GPR84 stimulation represents a promising therapeutic approach for treating NASH.
