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.

Multi‐compartment metabolomics and metagenomics reveal major hepatic and intestinal disturbances in cancer cachectic mice

“…62 In the C26 model, a functional test confirmed an increased hepatic protein synthesis. 63 In addition, we observed a reduction in the expression of Atg7 (L2FC: À0.53, q-value <0.001), a key regulator of autophagy, 64 and Smurf1 (L2FC: À0.42, qvalue <0.001), an important E3 ubiquitin protein ligase in the liver, 65 suggesting a reduction in protein degradation for nitrogen sparing. Atg7 was also decreased in another preclinical model of cachexia (LLC model) in which the authors reported a decrease in autophagy machinery with cancer progression.…”

Protein Quality Control and Lipid Droplet Metabolism

“…However, an LD-associated E3 ligase that cooperates with these factors and substrates for this putative degradation pathway has yet to be identified. AIP4/5, which are recruited to LDs by spartin (Eastman et al 2009, Edwards et al 2009, Hooper et al 2010, Tokunaga et al 2013, and SMURF1 (Petrasek et al 2019) have been proposed to function as LD-associated E3 ligases. These proteins have not been observed in most proteomic analyses of LD fractions, although their association may be lost during the biochemical isolation of LDs or be limited to specific cell types.…”

Study on autophagy-related biomarkers in pancreatic cancer based on bioinformatics

“…Promotes ubiquitination and subsequent proteasome degradation of MAVS [33]. SMURF1 regulates selective autophagy by ubiquitinating proteins used for autophagy delivery to cargo for lysosomal degradation [34]. ITGA3 is an integrin subunit alpha 3 receptor for fibronectin, laminin, collagen, epiligrin, thrombospondin and CSPG4, it provides a dock site for FAP (seprase) in the invading pseudopod plasma membrane in a collagen-dependent manner, and therefore may participate in the process of adhesion, formation of invasive pseudopod and stroma degradation to promote cell invasion.…”