title: Triacylglycerol accumulation activates the mitochondrial apoptosis pathway in macrophages.
abstract: Programmed cell death of lipid-laden macrophages is a prominent feature of atherosclerotic lesions and mostly ascribed to accumulation of excess intracellular cholesterol. The present in vitro study investigated whether intracellular triacylglycerol (TG) accumulation could activate a similar apoptotic response in macrophages. To address this question, we utilized peritoneal macrophages isolated from mice lacking adipose triglyceride lipase (ATGL), the major enzyme responsible for TG hydrolysis in multiple tissues. In Atgl(-/-) macrophages, we observed elevated levels of cytosolic Ca(2+) and reactive oxygen species, stimulated cytochrome c release, and nuclear localization of apoptosis-inducing factor. Fragmented mitochondria prior to cell death were indicative of the mitochondrial apoptosis pathway being triggered as a consequence of defective lipolysis. Other typical markers of apoptosis, such as externalization of phosphatidylserine in the plasma membrane, caspase 3 and poly(ADP-ribose) polymerase cleavage, were increased in Atgl(-/-) macrophages. An artificial increase of cellular TG levels by incubating wild-type macrophages with very low density lipoprotein closely mimicked the apoptotic phenotype observed in Atgl(-/-) macrophages. Results obtained during the present study define a novel pathway linking intracellular TG accumulation to mitochondrial dysfunction and programmed cell death in macrophages.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria.
authors.forename: Elma
authors.initials: E
authors.lastname: Aflaki
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.forename: Julia
authors.initials: J
authors.lastname: Ring
authors.forename: Ismene
authors.initials: I
authors.lastname: Fertschai
authors.forename: Andreas
authors.initials: A
authors.lastname: Uellen
authors.forename: Heimo
authors.initials: H
authors.lastname: Wolinski
authors.forename: Sepp-Dieter
authors.initials: SD
authors.lastname: Kohlwein
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.forename: Roland
authors.initials: R
authors.lastname: Malli
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000378:metabolism; D005260:Female; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D051033:Apoptosis Inducing Factor; D015243:Cholesterol, VLDL; D008049:Lipase; D014280:Triglycerides; C494830:AIFM1 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases