In vivo experiments on ethanol-fed rodents reported animal-specific differences on the effects of ethanol on hepatic PPARα protein levels. In Sv/129 mice and in rats, ethanol administration decreased PPARα protein levels [41–43]. Activation of PPARα by clofibrate in ethanol-fed rats ameliorates fatty liver and decreased necroinflammatory injury [43]. On the other hand, in ethanol-fed C57BL/6J mice PPARα protein levels did not change substantially; however PPARα/RXR binding to DNA was significantly impaired and some PPARα target genes (as medium chain acyl CoA dehydrogenase) were downregulated [29]. Although the observed reduction in RXR protein level in ethanol-fed mice could certainly account for the reduced PPARα/RXR DNA binding, induction of PPARα alone by its agonist WY14,643 restored PPARα/RXR binding activity by inducing PPARα but not RXR protein levels, thus revealing that also a reduced activation of PPARα mediates the ethanol effects in vivo. The restored PPARα/RXR binding by WY14,643 administration to ethanol-fed mice was accompanied by an increase of the mRNA of PPARα target genes, some of which were actually either not downregulated by ethanol feeding, such as acyl-CoA oxidase, carnitine palmitoyl transferase-1
