Protective Effect of SMAD‐Specific E3 Ubiquitin Protein Ligase 1 in Alcoholic Steatohepatitis in Mice

Abstract

Excessive accumulation of lipids in the liver is crucial in the pathogenesis of alcoholic steatohepatitis and may be partly mediated by impaired degradation of lipid droplets by autophagy. The E3 ubiquitin ligase SMAD‐specific E3 ubiquitin protein ligase 1 (SMURF1) regulates selective autophagy by ubiquitinating proteins on cargo destined for autophagic delivery to the lysosome for degradation. Here, we evaluated the role of SMURF1 in the regulation of hepatic lipid degradation in alcoholic steatohepatitis. In patients with severe alcoholic hepatitis, SMURF1 colocalized with lipid droplet membranes in liver explants. In a mouse model of alcoholic steatohepatitis, Smurf1−/− mice fed an alcohol diet displayed increased hepatocyte accumulation of lipid droplets and triglycerides as well as more severe liver injury compared to wild‐type mice. The increased severity of liver steatosis in alcohol‐fed Smurf1−/− mice was rescued by adeno‐associated virus (AAV) serotype 8‐mediated hepatic expression of wild‐type Smurf1 protein but not by mutant Smurf1 proteins either lacking the catalytically active cysteine 699 required for ubiquitin transfer or the N‐terminal C2 phospholipid membrane‐binding domain. Conclusion: Smurf1 plays a protective role in the pathogenesis of alcoholic steatohepatitis through a mechanism that requires both its ubiquitin‐ligase activity and C2 phospholipid‐binding domains. These findings have implications for understanding the roles of ubiquitin ligases in fatty liver disease.