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

Toxicology. 2017 Mar 15:379:12-21. doi: 10.1016/j.tox.2017.01.016. Epub 2017 Jan 25.

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.

Keywords: Alcoholic fatty liver; CYP2A5; FGF21; PPARα.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • 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