Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Cell Death Dis. 2020 Apr 24;11(4):283. doi: 10.1038/s41419-020-2472-6.
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.
非酒精性脂肪性肝病 (NAFLD) 是脂肪性肝炎、肝硬变和肝癌进展的一个危险因素。尽管源自肝脏中甘油三酯过度积累的 NAFLD 的病理状况伴随着固醇调节元件结合蛋白 1c (SREBP1c) 水平的升高，但很大程度上尚不清楚哪些因素参与了 SREBP1c 的修饰。在这项研究中，我们发现 SREBP1c 的连接酶反应（neddylation）与其泛素化作用竞争，并稳定 SREBP1c 蛋白水平，最终促进肝脂肪变性。我们还证明了小鼠双微体 2 同源物 (HDM2) 作为 SREBP1c 的 E3 连接酶反应酶。此外，用连接酶反应抑制剂 MLN4924 处理可通过降低 SREBP1c 蛋白和肝甘油三酯水平来减轻高脂肪饮食诱导的肝脂肪变性。我们的结果表明，阻断 SREBP1c 的连接酶反应可能是防治 NAFLD 的一种新方法。
