Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis.
- Authors
- Chen, Xue; Ward, Stephen C; Cederbaum, Arthur I; Xiong, Huabao; Lu, Yongke
- Year
- 2017
- Journal
- Toxicology
- PMID
- 28131861
- DOI
- 10.1016/j.tox.2017.01.016
- PMCID
- PMC5319905
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.
Chronic ethanol-induced fatty liver is more pronounced in Cyp2a5−/− mice. (A) H&E staining. (B) Steatosis quantification (N=5). (C) Liver and serum TG (N=5). (D) Expression of CYP2A5, PI3K, AKT, and IRS by Western blotting analyses. (E) Quantitation of Western blots (N=4). *P<0.05, compared to Cyp2a5+/+ Control Group; # P<0.05, compared to Cyp2a5−/− Control Group; & P<0.05, compared with Cyp2a5+/+ Ethanol group. Cont, Control; EtOH, Ethanol.
Chronic ethanol induces FGF21 in Cyp2a5+/+ mice but does not in Cyp2a5−/− mice. (A) Serum FGF21 (N=5). (B) Liver expression of FGF21 and PPARα by Western blotting analysis. (C) Quantitation of Western blots (N=4). *P<0.05, compared to Cyp2a5+/+ Control Group. Cont, Control; EtOH, Ethanol.
Chronic ethanol induces FGF21 in Nrf2+/+ mice more than in Nrf2−/− mice. (A) Western blots. (B) Quantitation of Western blots (N=3). *P<0.05, compared to Nrf2+/+ Control Group; # P<0.05, compared to Nrf2−/− Control Group; & P<0.05, compared with Nrf2+/+ Ethanol group. Cont, Control; EtOH, Ethanol.
Recombinant FGF21 blunts ethanol-induced hypertriglyceridemia (HTG) in Pparα−/− mice. (A) Ethanol induction of FGF21 was blunted in Pparα−/− mice (N=5). (B) rFGF21 blunted ethanol-induced elevation of liver TG in WT mice but not in Pparα−/− mice (N=5). (C) rFGF21 blunted ethanol-induced HTG in Pparα−/− mice (N=5). (D) Ethanol induction of CYP2E1 and CYP2A5 was not affected in both Pparα+/+ and Pparα−/− mice (N=5). *P<0.05, compared to Control Group. # P<0.05, compared to WT Ethanol Group. $ P<0.05, compared to WT Control Group. ^ P<0.05, compared with PPARα KO Ethanol group. E+F, ethanol plus rFGF21; WT, wild-type; PPARα KO, Pparα−/−.
Alcoholic fatty liver is enhanced in Fgf21alb-cre mice but is not in Fr1alb-cre mice. (A) Ethanol induction of FGF21 was blunted in Fgf21alb-cre mice but was not in Fr1alb-cre mice (N=5). (B) H&E staining in liver sections shows that alcoholic fatty liver was enhanced in Fgf21alb-cre mice but not in Fr1alb-cre mice. (C) Steatosis scores (N=5). (D) Liver TG contents (N=5). *P<0.05, compared to Fr1fl/fl Control Group. # P<0.05, compared to Fgf21fl/fl Ethanol Group. ^ P<0.05, compared with Fgf21fl/fl control group. $ P<0.05, compared to Fr1alb-cre Control Group. @ P<0.05, compared to Fr1alb-cre Control Group. Cont, Control; EtOH, Ethanol.
Alcoholic fatty liver is more pronounced in Pparα−/−/Cyp2a5−/− mice than in Pparα+/+/Cyp2a5−/− mice. (A) Ethanol induction of FGF21 was blunted in Pparα−/−/Cyp2a5−/− mice (N=4). (B) H&E staining in liver sections shows that alcoholic fatty liver was more pronounced in Pparα−/−/Cyp2a5−/− mice than in Pparα+/+/Cyp2a5−/− mice. (C) Steatosis scores (N=5). (D) Liver TG contents (N=5). *P<0.05, compared to Pparα+/+/Cyp2a5−/− Control Group. # P<0.05, compared to Pparα−/−/Cyp2a5−/− Control Group. & P<0.05, compared to Pparα+/+/Cyp2a5−/− Ethanol Group. Cont, Control; EtOH, Ethanol.
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