The role of retinoid X receptor α in regulating alcohol metabolism

There is substantial overlap in retinol and alcohol metabolism. Mice that lack retinoic acid (RA) receptor retinoid X receptor α (RXRα) expression in the liver are more susceptible to alcoholic liver disease. To investigate the interaction between RXRα and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXRα-deficient [RXRα knockout (KO)] mice. Hepatocyte RXRα deficiency resulted in a significant increase in hepatic alcohol dehydrogenase (ADH) activity, ADH1 protein, but not Adh1 mRNA. Polysomal distribution analysis indicated that more polysome-associated Adh1 mRNA was present in the mutant mouse livers, suggesting increased ADH1 protein synthesis in RXRα KO mice compared with wild-type mice. However, ADH2 and ADH3 enzyme activities were not affected by RXRα deficiency. Although ethanol clearance was increased, acetaldehyde elimination was reduced when RXRα was not expressed in the liver. Both mitochondrial aldehyde dehydrogenase (ALDH) 2 and cytosolic ALDH activities were reduced in the mutant mice compared with the wild type. Western blot analysis revealed that the levels of ALDH1A1 and ALDH1A2 were decreased in the mutant mice. Semiquantitative reverse transcriptase-polymerase chain reaction indicated that liver Aldh1a1 mRNA level was also reduced due to the lack of RXRα expression. Thus, RXRα differentially affects ADH and ALDH activity, leading to an increase in alcohol clearance, but a reduction in acetaldehyde elimination. In addition, CYP2E1 as well as mitochondrial and cytosolic glutathione S-transferase activities were significantly lower in RXRα KO mice than in wild-type mice. Our results reveal the central role of RXRα in ethanol metabolism.