USP13 ameliorates metabolic dysfunction-associated steatohepatitis through targeting PTEN

Min Tang; Xiaohui Wei; Yunqin Ma; Yijiong Tan; Han Cao; Shuangshuang Yao; Jiaqi Wang; Hua Yang; Fang Liu; Yongde Peng; Nengguang Fan

doi:10.1016/j.lfs.2024.123264

USP13 ameliorates metabolic dysfunction-associated steatohepatitis through targeting PTEN

Life Sci. 2024 Nov 19:123264. doi: 10.1016/j.lfs.2024.123264. Online ahead of print.

Authors

Min Tang¹, Xiaohui Wei², Yunqin Ma², Yijiong Tan³, Han Cao⁴, Shuangshuang Yao², Jiaqi Wang², Hua Yang⁵, Fang Liu², Yongde Peng⁶, Nengguang Fan⁷

Affiliations

¹ Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Endocrinology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, Shanghai, China; Department of Endocrinology, Songjiang District Central Hospital, Shanghai, China.
⁵ Department of Endocrinology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁶ Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, Shanghai, China. Electronic address: qingyun5chen@sjtu.edu.cn.
⁷ Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: 72400015171@shsmu.edu.cn.

PMID: 39571890
DOI: 10.1016/j.lfs.2024.123264

Abstract

Objective: The role of ubiquitin-specific protease 13 (USP13) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to elucidate the role of USP13 in MASH progression.

Methods: THLE-2 cells were subjected to palmitate acid (PA) to generate an in vitro model of lipid accumulation and inflammation. Two in vivo models of MASH were established by feeding mice with a high-fat, high-fructose and high-cholesterol (HFFC) diet for 16 weeks and a methionine/choline-deficient diet (MCD) for 4 weeks, respectively. Usp13 overexpression and knockout (KO) techniques were employed to investigate its role in MASH.

Results: USP13 expression was significantly downregulated in the livers of MASH mice and in the in vitro model of lipid accumulation and inflammation. Hepatic overexpression of Usp13 markedly alleviated liver steatosis, inflammation and fibrosis, while knockout of Usp13 exacerbated the MASH phenotype. Mechanistically, USP13 directly bound to phosphatase and tensin homolog (PTEN) and deubiquitinated it, thereby elevating the PTEN expression and improving the MASH phenotype. Notably, Pten overexpression in Usp13 knockout mice reversed the exacerbation of MASH brought from Usp13 deficiency.

Conclusions: Our findings revealed that USP13 alleviates MASH by directly binding to and deubiquitinating PTEN. The USP13-PTEN axis may represent a promising molecular target for MASH treatment.

Keywords: Deubiquitination; Metabolic dysfunction-associated steatohepatitis; Phosphatase and tensin homolog; Ubiquitin-specific protease 13.