To investigate whether the basal upregulation of PPARα-FGF21 in Cyp2a5−/− mice protects against alcoholic fatty liver, we designed a model to abrogate the upregulation of PPARα in Cyp2a5−/− mice by creating Pparα−/−/Cyp2a5−/− mice. A comparison between Pparα−/−/Cyp2a5−/− mice and Pparα+/+/Cyp2a5−/− mice would help to define the role of PPARα-FGF21 in the enhanced alcoholic fatty liver in Cyp2a5−/− mice. As shown in Fig 6A, serum FGF21 was much lower in Pparα−/−/Cyp2a5−/− mice than in Pparα+/+/Cyp2a5−/− mice; ethanol feeding increased serum FGF21 in Pparα+/+/Cyp2a5−/− mice but did not in Pparα−/−/Cyp2a5−/− mice. Alcoholic fatty liver was more pronounced in Pparα−/−/Cyp2a5−/− mice than in Pparα+/+/Cyp2a5−/− mice (Fig 6B, C), and liver TG accumulation was also higher in Pparα−/−/Cyp2a5−/− mice than in Pparα+/+/Cyp2a5−/− mice (Fig 6D), suggesting that abrogating the upregulation of the PPARα-FGF21 axis enhances alcoholic fatty liver; and the difference in alcoholic fatty liver between Cyp2a5−/− mice and Cyp2a5+/+ mice might be due to the inability of ethanol to upregulate the PPARα-FGF21 axis in Cyp2a5−/− mice.
