RXRalpha-regulated liver SAMe and GSH levels influence susceptibility to alcohol-induced hepatotoxicity

Retinoids influence the pathogenesis of alcohol liver disease (ALD). To analyze the impact of retinoid X receptor alpha (RXRalpha) on ALD, alcohol-induced hepatotoxicity was studied using mice fed ethanol intragastrically for 25 days. Alcohol-induced microvesicular fat around the central vein and drug-induced morphological changes (loss of rough endoplasmic reticulum, pinkish cytoplasm, and enlarged hepatocyte) in the pericentral area were observed in the liver of wild-type mice. In the hepatocyte RXRalpha-deficient mouse liver, alcohol induced fat accumulation, mitosis, acute inflammation, and necrosis. The histology score after alcohol treatment was significantly higher in mutant mice than in wild-type mice. However, drug-induced morphological changes were not apparent in alcohol-treated hepatocyte RXRalpha-deficient mice. Northern analysis showed that the basal and alcohol-induced CYP2B, CYP2A, and CYP3A mRNA levels were lower in hepatocyte RXRalpha-deficient mice than in wild-type mice, which in turn may protect mutant mice from morphological changes. Compared with wild-type mice, hepatocyte RXRalpha-deficient mice have significant lower levels of S-adenosylmethionine and glutathione, which is further reduced after alcohol treatment, and that may account for severe liver injury induced by alcohol. The overall result suggests an important role of RXRalpha in preventing alcohol-induced liver injury.