Abstract
BackgroundAlcohol abuse and alcoholism lead to alcohol liver disease such as alcoholic fatty liver. Parkin is a component of the multiprotein E3 ubiquitin ligase complex and is associated with hepatic lipid accumulation. However, the role of parkin in ethanol-induced liver disease has not been reported. Here, we tested the effect of parkin on ethanol-induced fatty liver in parkin knockout (KO) mice with chronic ethanol feeding.MethodsMale wild type (WT) and parkin KO mice (10–12 weeks old, n = 10) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 10 days. Liver histological, biochemical, and gene-expression studies were performed.ResultsParkin KO mice exhibited lower hepatosteatosis after ethanol consumption. Because several studies reported that β-catenin is a critical factor in ethanol metabolism and protects against alcohol-induced hepatosteatosis, we investigated whether parkin changes β-catenin accumulation in the liver of ethanol-fed mice. Our results show that β-catenin was greatly accumulated in the livers of ethanol-fed parkin KO mice compared to ethanol-fed WT mice, and that parkin binds to β-catenin and promotes its degradation it by ubiquitination. Moreover, the β-catenin inhibitor IWR-1 abrogated the attenuation of ethanol-induced hepatic lipid accumulation by parkin deficiency in the livers of parkin KO mice and parkin siRNA-transfected human hepatic cell line.ConclusionsParkin deficiency prevents ethanol-induced hepatic lipid accumulation through promotion of β-catenin signaling by failure of β-catenin degradation.
Highlights
Alcohol abuse and alcoholism lead to alcohol liver disease such as alcoholic fatty liver
Parkin-deficient mice exhibit attenuation of chronic ethanol-induced hepatosteatosis We examined the effects of parkin deletion on chronic ethanol-induced changes in body weight, liver cholesterol, liver triglycerides, and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
Parkin deficiency regulates the expression of genes involved in lipid metabolism Because parkin-deficient mice showed decreased lipid accumulation induced by ethanol diet in the liver, we investigated the effect of parkin deficiency in ethanol-treated mouse primary hepatic cells
Summary
Alcohol abuse and alcoholism lead to alcohol liver disease such as alcoholic fatty liver. The role of parkin in ethanol-induced liver disease has not been reported. Excessive and chronic alcohol consumption leads to alcoholic liver disease such as alcoholic fatty liver, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. The β-catenin signaling pathway is associated with cell survival under oxidative stress as well as hepatic metabolic zonation [4, 5]. Lehwald et al reported that β-catenin mediates hepatocyte protection in hypoxia or ischemia/reperfusion-induced oxidative injury of the liver [6]. Tao et al reported that Wnt/β-catenin signaling protects against oxidative stress-induced apoptosis in mouse liver [7]. These results suggest that β-catenin signaling may play a protective role in oxidative stress-induced liver injury.
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