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

作者：Chen Xue; Ward Stephen C; Cederbaum Arthur I; Xiong Huabao; Lu Yongke^*

来源：Toxicology, 2017, 379: 12-21.

DOI：10.1016/j.tox.2017.01.016

• CYP2A5
• FGF21
• PPAR alpha
• Alcoholic fatty liver

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 PPARce-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Ppara knockout (Ppar alpha(-/-)) mice. This study investigates the relationship between the PPARa-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 Ppara 1-mice than in Ppar alpha(+/+) mice; ethanol induced FGF21 in Ppara(+/+) mice but not in Ppar alpha(-/-) mice, whereas ethanol induced hypertriglyceridemia in Ppar alpha(-/-) mice but not in Ppar alpha(+/+) mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Ppar alpha(-/-) mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Ppara and Cyp2a5 double knockout (Ppara(-/-)/Cyp2a5(-/-)) mice developed more severe alcoholic fatty liver than Ppar(+/+)/Cyp2a5(-/-) mice.
Conclusions: These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARa-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease.

• 出版日期2017-3-15