Fat-1 Ameliorates Metabolic Dysfunction-Associated Fatty Liver Disease and Atherosclerosis through Promoting the Nuclear Localization of PPARα in Hamsters.

Abstract

Fat-1, an enzyme encoded by the fat-1 gene, is responsible for the conversion of endogenous omega-6 polyunsaturated fatty acids into omega-3 polyunsaturated fatty acids in Caenorhabditis elegans. To better investigate whether the expression of Fat-1 will exert a beneficial function in dyslipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD), we established an adeno-associated virus 9 expressing Fat-1. We found that adeno-associated-virus-mediated expression of Fat-1 markedly reduced the levels of plasma triglycerides and total cholesterol but increased high-density lipoprotein levels in male wild-type hamsters on both chow diet and high-fat diet as well as in chow-diet-fed male LDLR^-/- hamsters. Fat-1 ameliorated diet-induced MAFLD in wild-type hamsters by enhancing fatty acid oxidation through the hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent pathway. Mechanistically, Fat-1 increased the levels of multiple lipid derivatives as ligands for PPARα and simultaneously facilitated the nuclear localization of PPARα. Our results provide new insights into the multiple therapeutic potentials of Fat-1 to treat dyslipidemia, MAFLD, and atherosclerosis.