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2024

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08

Cell sub-journal | Lu Yan of Shanghai Jiaotong University and other teams have jointly revealed the important role of deubiquitinating enzyme RPN11 in improving nonalcoholic fatty liver disease!

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Nonalcoholic fatty liver disease (NAFLD), including its more severe form of nonalcoholic steatohepatitis (NASH), is a global public health challenge.

On August 14, 2024, Shanghai Jiaotong University Lu Yan, Hu Cheng, Li Yao and Fudan University Zhao Bing jointly communicated inCell Metabolism（IF=27.7）Published online entitled"Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11"'s research paper,The study foundInhibition of deubiquitinating enzyme RPN11 improves nonalcoholic fatty liver disease.

Hepatocyte-specific RPN11 knockout mice are protected against diet-induced hepatic steatosis, insulin resistance, and steatohepatitis. Mechanismically, RPN11 deubiquitinizes and stabilizes METTL3, enhances m6A modification and expression of acyl-CoA (CoA) synthetase short-chain family member 3 (ACSS3), and up-regulates lipid metabolism genes by generating propionyl-CoA through histone propionylation. In the liver of NAFLD patients, the RPN11-METTL3-ACSS3-histone propionylation pathway is activated. Pharmacological inhibition of RPN11 by Capzimin ameliorated NAFLD, NASH and related metabolic disorders in mice, reducing the lipid content of 2D and 3D cultured human hepatocytes.These results suggest that RPN11 is a novel regulator of NAFLD/NASH and that inhibition of RPN11 has therapeutic potential.

 

Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). With a global prevalence of 38.2 percent, NAFLD is the fastest growing cause of HCC, especially in the Americas. NAFLD is associated with metabolic disorders including insulin resistance, hyperglycemia and hyperlipidemia. Because of its close association with metabolic dysfunction, experts have recently recommended that NAFLD be redefined as metabolic dysfunction-associated steatosis liver disease (MASLD). This redefinition highlights the complex metabolic nature of the disease and the urgent need for new therapeutic targets to address its multifaceted pathology.

NAFLD/NASH is characterized by an excessive accumulation of hepatic triglycerides in hepatocytes, which is regulated by several transcription factors (TFs), such as SREBP-1c, ChREBP, LXRα, and PPARα.Although the role of TFs in hepatic lipid metabolism is well established, the impact of their post-translational modifications, including ubiquitination and deubiquitination, is unclear.Ubiquitin (Ub) is a conserved protein that attaches to lysine residues on cellular proteins for proteasomal degradation, signal transduction, and gene transcription. This modification is reversible and is catalyzed by deubiquitinating enzymes (DUBs), which remove Ub to stabilize the protein. Approximately 100 DUBs have been identified as being associated with health and disease, including cancer and inflammation. Because DUBs have a well-defined active site, with several inhibitors in preclinical and clinical trials for cancer, DUBs are emerging as therapeutic targets. However, their potential to treat NAFLD/NASH remains largely unexplored,

In this study, we explored the role of RPN11 in NAFLD/NASH using genetic and pharmacological approaches. RPN11 HKO mice were unaffected by diet-induced hepatic steatosis, insulin resistance, and steatohepatitis. Mechanically, proteomics and IP-MS identified METTL3 as a substrate for RPN11. Reintroduction of METTL3 reversed the metabolic profile of RPN11 HKO mice.

Together, this study reveals a role for the RPN11-METTL3-ACSS3-histone propionation pathway in promoting NAFLD, NASH, and insulin resistance.These findings not only advance the understanding of the pathophysiology of NAFLD/NASH, but also suggest pharmacological inhibitors of RPN11, such as Capzimin, as a potential therapeutic strategy.

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