title: Functional cardiac lipolysis in mice critically depends on comparative gene identification-58.
abstract: Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL.
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Kathrin A
authors: KA
authors: Zierler
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Doris
authors: D
authors: Jaeger
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Nina M
authors: NM
authors: Pollak
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Sandra
authors: S
authors: Eder
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Gerald N
authors: GN
authors: Rechberger
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Franz P W
authors: FPW
authors: Radner
authors: Department of Pharmacology and Toxicology, University of Graz, 8010 Graz, Austria.
authors: Gerald
authors: G
authors: Woelkart
authors: Center for Medical Research, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
authors: Dagmar
authors: D
authors: Kolb
authors: Department of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
authors: Albrecht
authors: A
authors: Schmidt
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Manju
authors: M
authors: Kumari
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Karina
authors: K
authors: Preiss-Landl
authors: Department of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
authors: Burkert
authors: B
authors: Pieske
authors: Department of Pharmacology and Toxicology, University of Graz, 8010 Graz, Austria.
authors: Bernd
authors: B
authors: Mayer
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Robert
authors: R
authors: Zimmermann
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Achim
authors: A
authors: Lass
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria. Electronic address: guenter.haemmerle@uni-graz.at.
authors: Rudolf
authors: R
authors: Zechner
authors: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors: Guenter
authors: G
authors: Haemmerle
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism; D004452:Echocardiography / Q000379:methods; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006868:Hydrolysis; D008049:Lipase / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis / Q000502:physiology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009132:Muscles / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D005947:Glucose; D008049:Lipase; D008055:Lipids; D014280:Triglycerides; C492986:Abhd5 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases