Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha.

Normal function of the peroxisome proliferator-activated receptor alpha (PPARalpha) is crucial for the regulation of hepatic fatty acid metabolism. Fatty acids serve as ligands for PPARalpha, and when fatty acid levels increase, activation of PPARalpha induces a battery of fatty acid-metabolizing enzymes to restore fatty acid levels to normal. Hepatic fatty acid levels are increased during ethanol consumption. However, results of in vitro work showed that ethanol metabolism inhibited the ability of PPARalpha to bind DNA and activate reporter genes. This observation has been further studied in mice. Four weeks of ethanol feeding of C57BL/6J mice also impairs fatty acid catabolism in liver by blocking PPARalpha-mediated responses. Ethanol feeding decreased the level of retinoid X receptor alpha (RXRalpha) as well as the ability of PPARalpha/RXR in liver nuclear extracts to bind its consensus sequence, and the levels of mRNAs for several PPARalpha-regulated genes were reduced [long-chain acyl coenzyme A (acyl-CoA) dehydrogenase and medium-chain acyl-CoA dehydrogenase] or failed to be induced (acyl-CoA dehydrogenase, liver carnitine palmitoyl-CoA transferase I, very long-chain acyl-CoA synthetase, very long-chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals. Consistent with this finding, ethanol feeding did not induce the rate of fatty acid beta-oxidation, as assayed in liver homogenates. Inclusion of WY14,643, a PPARalpha agonist, in the diet restored the DNA-binding activity of PPARalpha/RXR, induced mRNA levels of several PPARalpha target genes, stimulated the rate of fatty acid beta-oxidation in liver homogenates, and prevented fatty liver in ethanol-fed animals. Blockade of PPARalpha function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by WY14,643.