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

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) including its more severe manifestation, nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we reveal a role for the deubiquitinating enzyme RPN11 in the development of NAFLD and NASH. Ablation of hepatic RPN11 markedly protected mice from several diets-induced liver steatosis, insulin resistance and steatohepatitis, whereas RPN11 overexpression had the opposite effects. Mechanistically, RPN11 interacts with and stabilizes METTL3 via deubiquitination initiated at lysine 241, to increase the m6A modification and expression of acyl-CoA synthetase short chain family member 3 (ACSS3). RPN11-ACSS3 axis generates propionyl-CoA and functions in histone propionylation to transcriptionally upregulate lipid metabolism-related genes. Of pathophysiological significance, RPN11-METTL3-ACSS3-histone propionylation modification pathway is activated in the livers of patients with NAFLD. More importantly, pharmacological inhibition of RPN11 by Capzimin showed dramatic beneficial effects in ameliorating NAFLD, NASH and related metabolic disorders in mice. Capzimin also reduces intracellular lipid contents in human primary hepatocytes cultured in 2D and 3D spheroids. Together, these results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Yan Lu

PROVIDER: PXD053163 | iProX | Sat Jun 15 00:00:00 BST 2024

REPOSITORIES: iProX

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

Zhou Bing B Luo Yunchen Y Bi Hanqi H Zhang Ni N Ma Mingyue M Dong Zhixia Z Ji Nana N Zhang Shuo S Wang Xiaoye X Liu Yuejun Y Guo Xiaozhen X Wei Wei W Xie Cen C Wu Ling L Wan Xinjian X Zheng Ming-Hua MH Zhao Bing B Li Yao Y Hu Cheng C Lu Yan Y

Cell metabolism 20240814 10

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) syn ...[more]

PMID: 39146936

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Project description:A time course of the effect of overexpressing GPI-PLD on global gene expression in HepG2 cells was compared to control virus. Experiment Overall Design: This experiment compares the global gene expression in HepG2 cells that were either transduced with an adenovirus expressing GPI-phospholipase D or an adenovirus expressing beta galactosidase as a control. Treatment was for 6 or 12 hrs. Four replicates for each condition were used. 10 micrograms of total RNA was assayed per genechip using standard Affymetrix protocols. CONTEXT: Recent studies demonstrated that de novo lipogenesis is increased in patients with nonalcoholic fatty liver disease (NAFLD). Patients with NAFLD also have plasma lipid abnormalities. These lipid abnormalities may in part be related to insulin resistance, which is common in patients with NAFLD. Insulin resistance is associated with alterations in proteins involved in lipid metabolism including glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), which is involved in triglyceride metabolism. OBJECTIVE: The objective of the study was to determine whether alterations in serum and hepatic levels of GPI-PLD occur in patients with NAFLD. DESIGN AND PATIENTS: We examined the following: 1) levels of serum GPI-PLD in nondiabetics with nonalcoholic steatohepatitis, compared with matched controls; 2) hepatic expression of GPI-PLD mRNA in patients with normal liver or NAFLD; and 3) effect of overexpressing GPI-PLD vs. beta-galactosidase (control) on global gene expression in a human hepatoma cell line. RESULTS: The serum levels of GPI-PLD were significantly higher in patients with nonalcoholic steatohepatitis than in matched controls (119 +/- 24 vs.105 +/- 15 microg/ml, P = 0.047). The hepatic expression of GPI-PLD mRNA was increased nearly 3-fold in NAFLD patients, compared with patients with normal liver (3.1 +/- 2.6 vs. 1.1 +/- 1.0 arbitrary units per microgram total RNA, P = 0.026). Finally, overexpressing GPI-PLD was associated with an increase in de novo lipogenesis genes. CONCLUSIONS: Patients with NAFLD have elevated serum levels and hepatic expression of GPI-PLD, and its overexpression in vitro is associated with increased expression of de novo lipogenesis genes. These results suggest that GPI-PLD may play a role in the pathogenesis of NAFLD and/or its metabolic features and warrants further investigation.

Dataset Information

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

Publications

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

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