title: Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation.
abstract: Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA; Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9077, USA.
authors.forename: Caleb C
authors.initials: CC
authors.lastname: Lord
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.
authors.forename: Gwynneth
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Schugar
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Burrows
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Gromovsky
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Betters
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Chase
authors.initials: C
authors.lastname: Neumann
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sacks
authors.affiliation: Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2R3, Canada.
authors.forename: Russell
authors.initials: R
authors.lastname: Watts
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Takuya F
authors.initials: TF
authors.lastname: Sakaguchi
authors.affiliation: Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2R3, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Lehner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: brownm5@ccf.org.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D004075:Diglycerides / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008049:Lipase / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology; D008066:Lipolysis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D004075:Diglycerides; D008049:Lipase; D014280:Triglycerides; C492986:Abhd5 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: lipase; neutral lipid storage disease; triacylglycerol