Dataset Information

β-catenin ISGylation promotes lipid deposition and apoptosis in ethanol-stimulated liver injury models.

ABSTRACT:

Background

The restoration of the Wnt/β-catenin pathway to alleviate alcoholic fatty liver disease (AFLD) progression is under study as a new strategy for alcoholic liver disease (ALD) treatment. Recent studies have indicated that interferon-stimulated gene 15 (ISG15) can covalently bind to β-catenin by HECT E3 ubiquitin ligase 5 (HERC5), leading to ISG degradation and downregulation of β-catenin levels. However, the relationship between β-catenin and the ISG15 system in AFLD remains unclear.

Methods

Here, we explored the roles of the ISG15 system in β-catenin activation and in the pathogenesis of alcohol-induced liver injury and steatosis.

Results

In this study, HERC5 silencing upregulated β-catenin protein expression and inhibited lipid metabolism disorders and cell apoptosis. Reduced β-catenin protein expression, increased lipid metabolism disorders, and cell apoptosis were detected in cells induced with HERC5 overexpression, which was reversible with the reactive oxygen species (ROS) inhibitor. All the above results were statistically analyzed. Thus, these observations demonstrate that β-catenin ISGylation is a prominent regulator of ALD pathology, which works by regulating ROS to induce lipid metabolism disorders and cell apoptosis.

Conclusion

Our findings provided the mechanism involved in the β-catenin ISGylation, allowing for future studies on the prevention or amelioration of liver injury in ALD.

SUBMITTER: Ding Q

PROVIDER: S-EPMC9586657 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

β-catenin ISGylation promotes lipid deposition and apoptosis in ethanol-stimulated liver injury models.

Ding Qi Q Zhang Guodong G Wang Yang Y Xu Lei L Wu Meifei M Zhou Yiwen Y Xu Tao T Meng Xiaoming X Huang Cheng C Zhang Lei L

Redox report : communications in free radical research 20221201 1

<h4>Background</h4>The restoration of the Wnt/β-catenin pathway to alleviate alcoholic fatty liver disease (AFLD) progression is under study as a new strategy for alcoholic liver disease (ALD) treatment. Recent studies have indicated that interferon-stimulated gene 15 (ISG15) can covalently bind to β-catenin by HECT E3 ubiquitin ligase 5 (HERC5), leading to ISG degradation and downregulation of β-catenin levels. However, the relationship between β-catenin and the ISG15 system in AFLD remains unc ...[more]

PMID: 36259544

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Project description:Prolonged exposure of mice to diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in hepatobiliary injury, atypical ductular proliferation, oval cell appearance, and limited fibrosis. Previously, we reported that short-term ingestion of DDC diet by hepatocyte-specific ?-catenin conditional knockout (KO) mice led to fewer A6-positive oval cells than wildtype (WT) littermates. To examine the role of ?-catenin in chronic hepatic injury and repair, we exposed WT and KO mice to DDC for 80 and 150 days. Paradoxically, long-term DDC exposure led to significantly more A6-positive cells, indicating greater atypical ductular proliferation in KO, which coincided with increased fibrosis and cholestasis. Surprisingly, at 80 and 150 days in KO we observed a significant amelioration of hepatocyte injury. This coincided with extensive repopulation of ?-catenin null livers with ?-catenin-positive hepatocytes at 150 days, which was preceded by appearance of ?-catenin-positive hepatocyte clusters at 80 days and a few ?-catenin-positive hepatocytes at earlier times. Intriguingly, occasional ?-catenin-positive hepatocytes that were negative for progenitor markers were also observed at baseline in the KO livers, suggesting spontaneous escape from cre-mediated recombination. These cells with hepatocyte morphology expressed mature hepatocyte markers but lacked markers of hepatic progenitors. The gradual repopulation of KO livers with ?-catenin-positive hepatocytes occurred only following DDC injury and coincided with a progressive loss of hepatic cre-recombinase expression. A few ?-catenin-positive cholangiocytes were observed albeit only after long-term DDC exposure and trailed the appearance of ?-catenin-positive hepatocytes.In a chronic liver injury model, ?-catenin-positive hepatocytes exhibit growth and survival advantages and repopulate KO livers, eventually limiting hepatic injury and dysfunction despite increased fibrosis and intrahepatic cholestasis.

Dataset Information

β-catenin ISGylation promotes lipid deposition and apoptosis in ethanol-stimulated liver injury models.

Background

Methods

Results

Conclusion

Publications

β-catenin ISGylation promotes lipid deposition and apoptosis in ethanol-stimulated liver injury models.

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