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.
Department of Endocrinology and Metabolism, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
Cell Metab. 2024 Oct 1;36(10):2228-2244.e7. doi: 10.1016/j.cmet.2024.07.014. Epub 2024 Aug 14.
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.
非酒精性脂肪性肝病（NAFLD），包括其更严重的表现形式非酒精性脂肪性肝炎（NASH），是一个全球性的公共健康挑战。在这里，我们探讨去泛素化酶 RPN11 在 NAFLD 和 NASH 中的作用。肝细胞特异性 RPN11 敲除小鼠可防止饮食诱导的肝脂肪变性、胰岛素抵抗和脂肪性肝炎。从机制上讲，RPN11 去泛素化并稳定 METTL3，以增强 m6A 修饰和酰基辅酶 A（CoA）合成酶短链家族成员 3（ACSS3）的表达，产生丙酰 CoA，通过组蛋白丙酰化上调脂质代谢基因。RPN11-METTL3-ACSS3-组蛋白丙酰化途径在 NAFLD 患者的肝脏中被激活。通过 Capzimin 抑制 RPN11 的药理作用可改善小鼠的 NAFLD、NASH 和相关代谢紊乱，并降低在 2D 和 3D 培养的人肝细胞中的脂质含量。这些结果表明，RPN11 是 NAFLD/NASH 的一个新的调节剂，抑制 RPN11 具有治疗潜力。
