Fenofibrate promotes erucic acid metabolism by peroxisome enzyme EHHADH activation alleviating high-fat diet-induced steatotic liver disease

Area of Science:

• Hepatology
• Metabolic Disorders
• Pharmacology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern.
• Long-chain fatty acid (LCFA) accumulation is a key feature of high-fat diet-induced MASLD.
• Fenofibrate's mechanism in treating MASLD remains unclear.

Purpose of the Study:

• To investigate fenofibrate's effect on hepatic steatosis.
• To elucidate the mechanism of fenofibrate in regulating fatty-acid metabolism.
• To identify key enzymes involved in fenofibrate's action.

Main Methods:

• In vivo and in vitro experiments using AML-12 cells.
• Treatment with fenofibrate and erucic acid (EA).
• Analysis of hepatic LCFA accumulation and enzyme expression.

Main Results:

• Fenofibrate significantly reduced hepatic LCFA accumulation, particularly erucic acid (EA).
• Fenofibrate enhanced EA metabolism in AML-12 cells, improving lipid accumulation.
• Peroxisome enzymes enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase were identified as key mediators.

Conclusions:

• Fenofibrate promotes LCFA oxidation by upregulating enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase.
• This mechanism offers a novel therapeutic strategy for high-fat diet-induced steatotic liver disease.
• Fenofibrate's role in treating MASLD warrants further clinical investigation.