title: Ubiquitin Ligase COP1 Controls Hepatic Fat Metabolism by Targeting ATGL for Degradation.
abstract: 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.
authors.affiliation: Division of Cell Biology and Physiology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Mainak
authors.initials: M
authors.lastname: Ghosh
authors.affiliation: Division of Cell Biology and Physiology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Sougata
authors.initials: S
authors.lastname: Niyogi
authors.affiliation: Division of Structural Biology and Bioinformatics, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Bhattacharyya
authors.affiliation: Division of Cell Biology and Physiology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Moumita
authors.initials: M
authors.lastname: Adak
authors.affiliation: Nuclear Medicine Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Nayak
authors.affiliation: Division of Structural Biology and Bioinformatics, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Division of Cell Biology and Physiology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata, India pc1@csiriicb.in partha.iicb@gmail.com.
authors.forename: Partha
authors.initials: P
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat / Q000009:adverse effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000217:Acyltransferases
chemical_list: D008049:Lipase; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C471981:COP1 protein, human; C471982:COP1 protein, mouse; C494794:PNPLA2 protein, human; D000217:Acyltransferases