title: Deletion of CGI-58 or adipose triglyceride lipase differently affects macrophage function and atherosclerosis.
abstract: Cellular TG stores are efficiently hydrolyzed by adipose TG lipase (ATGL). Its coactivator comparative gene identification-58 (CGI-58) strongly increases ATGL-mediated TG catabolism in cell culture experiments. To investigate the consequences of CGI-58 deficiency in murine macrophages, we generated mice with a targeted deletion of CGI-58 in myeloid cells (macCGI-58(-/-) mice). CGI-58(-/-) macrophages accumulate intracellular TG-rich lipid droplets and have decreased phagocytic capacity, comparable to ATGL(-/-) macrophages. In contrast to ATGL(-/-) macrophages, however, CGI-58(-/-) macrophages have intact mitochondria and show no indications of mitochondrial apoptosis and endoplasmic reticulum stress, suggesting that TG accumulation per se lacks a significant role in processes leading to mitochondrial dysfunction. Another notable difference is the fact that CGI-58(-/-) macrophages adopt an M1-like phenotype in vitro. Finally, we investigated atherosclerosis susceptibility in macCGI-58/ApoE-double KO (DKO) animals. In response to high-fat/high-cholesterol diet feeding, DKO animals showed comparable plaque formation as observed in ApoE(-/-) mice. In agreement, antisense oligonucleotide-mediated knockdown of CGI-58 in LDL receptor(-/-) mice did not alter atherosclerosis burden in the aortic root. These results suggest that macrophage function and atherosclerosis susceptibility differ fundamentally in these two animal models with disturbed TG catabolism, showing a more severe phenotype by ATGL deficiency.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Goeritzer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schlager
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Corina T
authors.initials: CT
authors.lastname: Madreiter
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rainer
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Gwynneth
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Caleb C
authors.initials: CC
authors.lastname: Lord
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sacks
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Vujic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sachdev
authors.affiliation: Center for Medical Research/Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D066292:Lipid Droplets / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D010587:Phagocytosis; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D008049:Lipase; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; C492986:Abhd5 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: comparative gene identification-58; inflammation; lipid droplets; storage diseases