Ubiquitin Ligase COP1 Controls Hepatic Fat Metabolism by Targeting ATGL for Degradation
Ubiquitin Ligase COP1 Controls Hepatic Fat Metabolism by Targeting ATGL for Degradation
复制标题
DOI：
10.2337/db16-0506
复制
发表时间：
2016-12-01
期刊：
影响因子：
7.7
通讯作者：
Chakrabartil, Partha
中科院分区：
文献类型：
--
作者：
Ghosh, Mainak;Niyogi, Sougata;Chakrabartil, Partha
肝脏脂质代谢的最佳控制对机体代谢健康至关重要。在肝脏中，脂肪甘油三酯脂肪酶（ATGL）是一种主要的三酰甘油（TAG）脂肪酶，控制着细胞内脂质转化的大部分。然而，ATGL表达的调控及其在肝脂质代谢中的功能意义，特别是在脂肪肝疾病的背景下，尚不清楚。我们发现E3泛素连接酶COP1（也称为RFWD2）结合到ATGL的共识VP基序上，并通过K-48连接的多泛素化作用将其靶向蛋白酶体降解，主要是在赖氨酸100残基上。因此，COP1是肝细胞TAG含量、脂肪酸动员和氧化的关键调节因子。此外，cop1介导的肝脂质代谢调节需要ATGL的最佳表达来实现其代谢结果。在体内，腺病毒介导的COP1的缺失改善了小鼠肝脏中高脂肪饮食诱导的脂肪变性，并改善了肝功能。因此，我们的研究为泛素-蛋白酶体系统对肝脏脂质代谢的调节提供了新的见解，并提示COP1可能是非酒精性脂肪肝的潜在治疗靶点。
Optimal control of hepatic lipid metabolism is critical for organismal metabolic fitness. In liver, adipose triglyceride lipase (ATGL) serves as a major triacylglycerol (TAG) lipase and controls the bulk of intracellular lipid turnover. However, regulation of ATGL expression and its functional implications in hepatic lipid metabolism, particularly in the context of fatty liver disease, is unclear. We show that E3 ubiquitin ligase COP1 (also known as RFWD2) binds to the consensus VP motif of ATGL and targets it for proteasomal degradation by K-48 linked polyubiquitination, predominantly at the lysine 100 residue. COP1 thus serves as a critical regulator of hepatocyte TAG content, fatty acid mobilization, and oxidation. Moreover, COP1-mediated regulation of hepatic lipid metabolism requires optimum ATGL expression for its metabolic outcome. In vivo, adenovirus-mediated depletion of COP1 ameliorates high fat diet-induced steatosis in mouse liver and improves liver function. Our study thus provides new insights into the regulation of hepatic lipid metabolism by the ubiquitin-proteasome system and suggests COP1 as a potential therapeutic target for nonalcoholic fatty liver disease.