Long-chain dicarboxylic acids play a critical role in inducing peroxisomal β-oxidation and hepatic triacylglycerol accumulation

Recent studies provide evidence that peroxisomal β-oxidation negatively regulates mitochondrial fatty acid oxidation, and induction of peroxisomal β-oxidation causes hepatic lipid accumulation. However, whether there exists a triggering mechanism inducing peroxisomal β-oxidation is not clear. Long-chain dicarboxylic acids are the product of mono fatty acids subjected to ω-oxidation, and both fatty acids ω-oxidation and peroxisomal β-oxidation are induced under ketogenic conditions, indicating there might be a crosstalk between. Here, we revealed that administration of long-chain dicarboxylic acids strongly induces peroxisomal fatty acids β-oxidation and causes hepatic steatosis in mice through the metabolites acetyl-CoA and hydrogen peroxide. Under ketogenic conditions, upregulation of fatty acids ω-oxidation resulted in increased generation of long-chain dicarboxylic acids and induction of peroxisomal β-oxidation, which causes hepatic accumulation of lipid droplets in animals. Inhibition of fatty acids ω-oxidation reduced long-chain dicarboxylic acids formation and significantly lowered peroxisomal β-oxidation and improved hepatic steatosis. Our results suggest that endogenous long-chain dicarboxylic acids act as triggering molecules inducing peroxisomal β-oxidation and hepatic triacylglycerol deposition. Targeting fatty acids ω-oxidation might be an effective pathway in treating fatty liver and related metabolic diseases through regulating peroxisomal β-oxidation.