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

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.

• Authors: Xue Chen, Stephen C Ward, Arthur I Cederbaum, Huabao Xiong, Yongke Lu
• Journal: Toxicology (Toxicology) Vol. 379 Pg. 12-21 (03 15 2017) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 28131861 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• PPAR alpha
• fibroblast growth factor 21
• Fibroblast Growth Factors
• Aryl Hydrocarbon Hydroxylases
• Cyp2a5 protein, mouse
• Cytochrome P450 Family 2

Topics

• Animals
• Aryl Hydrocarbon Hydroxylases (physiology)
• Cytochrome P450 Family 2 (physiology)
• Fatty Liver, Alcoholic (etiology, prevention & control)
• Female
• Fibroblast Growth Factors (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2 (physiology)
• PPAR alpha (physiology)