title: Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis.
abstract: 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.
  
  
  
  Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver.
  
  
  
  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.
  
  
  
  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.affiliation: Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN, United States.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ward
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
authors.affiliation: Division of Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN, United States; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States. Electronic address: luy004@etsu.edu.
authors.forename: Yongke
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D000072467:Cytochrome P450 Family 2 / Q000502:physiology*; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D047493:PPAR alpha / Q000502:physiology*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D000072467:Cytochrome P450 Family 2
keywords: Alcoholic fatty liver; CYP2A5; FGF21; PPARα