Central Hospital of Edong Healthcare Group, Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University, Huangshi, China.
Basic Medical School, Wuhan University, Wuhan, China.
Hepatology. 2018 Nov;68(5):1786-1803. doi: 10.1002/hep.30062. Epub 2018 Sep 17.
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high-fat diet (HFD)-induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate-induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte-specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10-regulated hepatic steatosis were further investigated in HFD-treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6.
非酒精性脂肪性肝病 (NAFLD) 的特征为肝脂肪变性、胰岛素抵抗和炎症，其发病机制尚不清楚。泛素特异性肽酶 10（USP10）是泛素特异性蛋白酶家族的成员，参与环境应激反应、肿瘤生长、炎症和细胞代谢。然而，USP10 在肝脂肪变性、胰岛素抵抗和炎症中的作用在很大程度上仍未得到探索。在非酒精性脂肪性肝病患者、高脂肪饮食（HFD）诱导肥胖的小鼠和遗传性肥胖（ob/ob）小鼠的肝脏以及棕榈酸诱导的肝细胞中检测到 USP10 的表达。通过 HFD 处理或遗传缺陷诱导的小鼠肝特异性 USP10 缺乏或过表达，研究了 USP10 在肝脂肪变性、胰岛素抵抗和炎症中的作用。进一步在 HFD 处理的小鼠中研究了 USP10 调节肝脂肪变性的分子机制。USP10 的表达在非酒精性脂肪性肝病患者和肥胖小鼠的脂肪肝以及棕榈酸处理的肝细胞中显著降低。USP10 缺乏加剧了 HFD 处理 12 周引起的代谢功能障碍。相反，USP10 过表达可显著抑制 HFD 处理后小鼠的代谢功能障碍，并抑制 ob/ob 小鼠非酒精性脂肪性肝病的发展。进一步的研究表明，USP10 通过与 Sirt6 相互作用并抑制其泛素化和降解来调节肝脂肪变性。Sirt6 过表达显著改善了 USP10 缺乏在肝脂肪变性、胰岛素抵抗和炎症中的作用。相反，Sirt6 缺乏降低了 USP10 过表达在 HFD 处理时的改善作用。结论：USP10 通过 Sirt6 抑制肝脂肪变性、胰岛素抵抗和炎症。
