Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis. (15th March 2017)

• Record Type: Journal Article
• Authors: Chen, Xue; Ward, Stephen C.; Cederbaum, Arthur I.; Xiong, Huabao; Lu, Yongke
• Is Part Of: Toxicology. Volume 379(2017)
• Page Start: 12
• Page End: 21
• Publication Date: 2017-03-15
• Subjects: CYP2A6 Cytochrome P450 2A6 -- CYP2E1 Cytochrome P450 2E1 -- Cyp2e1−/− mice Cyp2e1 knockout mice -- CYP2A5 Cytochrome P450 2A5 -- Cyp2a5−/− mice Cyp2a5 knockout mice -- NRF2 nuclear factor-erythroid 2-related factor 2 -- Nrf2−/− mice Nrf2 knockout mice -- PPARα peroxisome proliferator-activated receptor α -- Pparα−/− mice Pparα knockout mice -- FGF21 fibroblast growth factor 21 -- Pparα−/−/Cyp2a5−/− mice Pparα and Cyp2a5 double knockout mice -- Fgf21alb−cre mice liver specific Fgf21 knockout mice -- FR1 FGF receptor 1 -- Fr1alb−cre mice liver specific Fr1 knockout mice -- rFGF21 mouse recombinant FGF21 -- TG triglyceride -- KCL potassium chloride -- H&E hematoxylin and eosin -- COH coumarin 7-hydroxylase -- SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis -- PI3K/AKT phosphatidylinositol 3-kinase/Protein Kinase B -- IRS-1 insulin receptor substrate 1; CYP2A5 -- FGF21 -- PPARα -- Alcoholic fatty liver; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.01.016
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: 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.