| USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination |
| Sha Hu1, Zhouxiang Wang1, Kun Zhu1, Hongjie Shi1, Fang Qin1, Tuo Zhang1, Song tian1, Yanxiao Ji1, Jianqing Zhang2, Juanjuan Qin3, Zhigang She2, Xiaojing Zhang1, Peng Zhang1, Hongliang Li1,2,3,4 |
1Taikang Medical School (School of Basic Medical Sciences), Wuhan University, 430000Wuhan, China
2Department of Cardiology, Renmin Hospital of Wuhan University, 430000Wuhan, China
3Medical Science Research Center, Zhongnan Hospital of Wuhan University, 430000Wuhan, China
4State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China |
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Received: June 25, 2024 Revised: September 29, 2024 Accepted: October 2, 2024
*Sha Hu, Zhouxiang Wang and Kun Zhu contributed equally to this work. |
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| ABSTRACT |
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Background/Aims
Metabolic dysfunction–associated fatty liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific proteinase 29 (USP29) plays pivotal roles in hepatic ischemia‒reperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression.
Methods
USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes.
Results
USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with Acyl-CoA synthetase long chain family member 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5.
Conclusions
USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD. |
| KeyWords:
USP29, MASLD, ACSL5, Fatty acid β-oxidation, Deubiquitination |
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