Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Fatty-acid metabolism disorders, especially long-chain fatty acids (LCFA) accumulation, is the main pathological feature of high fat diet-induced MASLD. Fenofibrate is mainly used for the treatment of hyperlipidemia and metabolic disorders in clinical settings. In recent years, its therapeutic effect on MASLD has also been reported, but the mechanism is still unclear. Here, we aimed to investigate the effect and mechanism of fenofibrate on hepatic steatosis via fatty-acid metabolism regulation. It was found that fenofibrate strongly reduced hepatic LCFA accumulation, especially decreased the content of erucic acid (EA). In AML-12 cells treated with EA, fenofibrate improved hepatic lipid accumulation by accelerating EA metabolism. In vivo and in vitro experiments have proven that peroxidase enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase is the key enzyme of fenofibrate in promoting LCFA metabolism. This study confirmed that fenofibrate upregulated peroxisome enzyme enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase expression to promote LCFA oxidation, which provided a novel strategy for the treatment of high-fat diet-induced steatotic liver disease in clinical settings. SIGNIFICANCE STATEMENT: We found that long-chain fatty acid overload was a characteristic of high-fat diet-induced fatty liver, and fenofibrate ameliorated high-fat diet-induced fatty liver by upregulating enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase to promote the oxidation of long-chain fatty acids, especially erucic acid. This study may contribute to the use of fenofibrate in the treatment of fatty liver disease.
