Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis

Background & aims: Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5^−/−) mice develop more severe alcoholic fatty liver than Cyp2a5^+/+ mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Pparα knockout (Pparα^−/−) mice. This study investigates the relationship between the PPARα-FGF21 axis and the enhanced alcoholic fatty liver in Cyp2a5^−/− mice. Methods: Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver. Results: More severe alcoholic fatty liver disease was developed in Cyp2a5^−/− mice than in Cyp2a5^+/+ mice. Basal FGF21 levels were higher in Cyp2a5^−/− mice than in Cyp2a5^+/+ mice, but ethanol did not further increase the elevated FGF21 levels in Cyp2a5^−/− mice while FGF21 was induced by ethanol in Cyp2a5^+/+ mice. Basal levels of serum FGF21 were lower in Pparα^−/− mice than in Pparα^+/+ mice; ethanol induced FGF21 in Pparα^+/+ mice but not in Pparα^−/− mice, whereas ethanol induced hypertriglyceridemia in Pparα^−/− mice but not in Pparα^+/+ mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Pparα^−/− mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Pparα and Cyp2a5 double knockout (Pparα^−/−/Cyp2a5^−/−) mice developed more severe alcoholic fatty liver than Pparα^+/+/Cyp2a5^−/− mice. Conclusions: These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARα-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease.