Cell Reports
(Jul 2016)
Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation
Caleb C. Lord,
Daniel Ferguson,
Gwynneth Thomas,
Amanda L. Brown,
Rebecca C. Schugar,
Amy Burrows,
Anthony D. Gromovsky,
Jenna Betters,
Chase Neumann,
Jessica Sacks,
Stephanie Marshall,
Russell Watts,
Martina Schweiger,
Richard G. Lee,
Rosanne M. Crooke,
Mark J. Graham,
Justin D. Lathia,
Takuya F. Sakaguchi,
Richard Lehner,
Guenter Haemmerle,
Rudolf Zechner,
J. Mark Brown
Affiliations
Caleb C. Lord
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
Daniel Ferguson
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
Gwynneth Thomas
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
Amanda L. Brown
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
Rebecca C. Schugar
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Amy Burrows
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Anthony D. Gromovsky
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Jenna Betters
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
Chase Neumann
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Jessica Sacks
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Stephanie Marshall
Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA
Russell Watts
Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2R3, Canada
Martina Schweiger
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Richard G. Lee
Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Rosanne M. Crooke
Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Mark J. Graham
Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Justin D. Lathia
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Takuya F. Sakaguchi
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
Richard Lehner
Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2R3, Canada
Guenter Haemmerle
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
Rudolf Zechner
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
J. Mark Brown
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
DOI
https://doi.org/10.1016/j.celrep.2016.06.049
Journal volume & issue
Vol. 16,
no. 4
Abstract
Read online
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.
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