Xue Chen1, Stephen C Ward2, Arthur I Cederbaum3, Huabao Xiong4, Yongke Lu5. 1. Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN, United States. 2. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, United States. 3. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States. 4. Division of Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States. 5. 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.
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.
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.
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