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 (CPT-1), very-long chain acyl CoA dehydrogenase and synthetase, or even induced by ethanol, such as L-fatty acid binding protein (L-FABP) [29]. The induction of PPARα target genes by WY14,643 was accomplished even with concomitant administration of ethanol, indicating that this ligand prevents the effect of ethanol on PPARα, possibly by increasing the fraction of DNA-bound PPAR/RXR and thus minimizing the post-translational modifications of the PPARα DNA binding domain by acetaldehyde [2, 29]. PPARα activation by WY14,643 restored the fatty acid β-oxidation, normalized serum fatty acid and trygliceride levels, and prevented fatty liver in ethanol-fed mice.
