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 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 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 their meta bolic outcomes. In vivo, adenovirus-mediated depletion of COP1 ameliorates high fat diet (HFD) induced steatosis in mouse liver and improves liver function. Our study thus provides new insights into the regulation of hepatic lipid metabolism by ubiquitin-proteasome system (UPS) and suggests COP1 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD).
- Received April 25, 2016.
- Accepted September 13, 2016.
- © 2016 by the American Diabetes Association.