Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11

Bing Zhou; Yunchen Luo; Hanqi Bi; Ni Zhang; Mingyue Ma; Zhixia Dong; Nana Ji; Shuo Zhang; Xiaoye Wang; Yuejun Liu; Xiaozhen Guo; Wei Wei; Cen Xie; Ling Wu; Xinjian Wan; Ming-Hua Zheng; Bing Zhao; Yao Li; Cheng Hu; Yan Lu

doi:10.1016/j.cmet.2024.07.014

Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11

Cell Metab. 2024 Oct 1;36(10):2228-2244.e7. doi: 10.1016/j.cmet.2024.07.014. Epub 2024 Aug 14.

Authors

Bing Zhou¹, Yunchen Luo², Hanqi Bi³, Ni Zhang⁴, Mingyue Ma¹, Zhixia Dong³, Nana Ji³, Shuo Zhang³, Xiaoye Wang⁵, Yuejun Liu⁶, Xiaozhen Guo⁷, Wei Wei⁸, Cen Xie⁷, Ling Wu⁹, Xinjian Wan³, Ming-Hua Zheng⁴, Bing Zhao¹⁰, Yao Li¹¹, Cheng Hu¹², Yan Lu¹³

Affiliations

¹ Institute of Metabolism and Regenerative Medicine, Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Endocrinology and Metabolism, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
³ Institute of Metabolism and Regenerative Medicine, Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁶ Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁸ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
⁹ Department of Assisted Reproduction, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁰ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. Electronic address: bingzhao@fudan.edu.cn.
¹¹ Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: yao.li@shsmu.edu.cn.
¹² Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China. Electronic address: alfredhc@sjtu.edu.cn.
¹³ Institute of Metabolism and Regenerative Medicine, Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: luyan5011@shsmu.edu.cn.

PMID: 39146936
DOI: 10.1016/j.cmet.2024.07.014

Abstract

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we explore the role of deubiquitinating enzyme RPN11 in NAFLD and NASH. Hepatocyte-specific RPN11 knockout mice are protected from diet-induced liver steatosis, insulin resistance, and steatohepatitis. Mechanistically, RPN11 deubiquitinates and stabilizes METTL3 to enhance the m6A modification and expression of acyl-coenzyme A (CoA) synthetase short-chain family member 3 (ACSS3), which generates propionyl-CoA to upregulate lipid metabolism genes via histone propionylation. The RPN11-METTL3-ACSS3-histone propionylation pathway is activated in the livers of patients with NAFLD. Pharmacological inhibition of RPN11 by Capzimin ameliorated NAFLD, NASH, and related metabolic disorders in mice and reduced lipid contents in human hepatocytes cultured in 2D and 3D. These results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.

Keywords: N6-methyladenosine methylation; deubiquitination; histone propionylation; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis.

MeSH terms

Animals
Deubiquitinating Enzymes / antagonists & inhibitors
Deubiquitinating Enzymes / metabolism
Hepatocytes / metabolism
Humans
Lipid Metabolism / drug effects
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / metabolism
Non-alcoholic Fatty Liver Disease* / pathology
Proteasome Endopeptidase Complex* / metabolism
Trans-Activators* / metabolism
Ubiquitination

Substances

Deubiquitinating Enzymes
Proteasome Endopeptidase Complex
Trans-Activators