title: Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase.
abstract: Macrophage phagocytosis is an essential biological process in host defense and requires large amounts of energy. To date, glucose is believed to represent the prime substrate for ATP production in macrophages. To investigate the relative contribution of free fatty acids (FFAs) in this process, we determined the phagocytosis rates in normal mouse macrophages and macrophages of adipose triglyceride lipase (ATGL)-deficient mice. ATGL was shown to be the rate-limiting enzyme for the hydrolysis of lipid droplet-associated triacylglycerol (TG) in many tissues. Here, we demonstrate that Atgl(-/-) macrophages fail to efficiently hydrolyze cellular TG stores leading to decreased cellular FFA concentrations and concomitant accumulation of lipid droplets, even in the absence of exogenous lipid loading. The reduced availability of FFAs results in decreased cellular ATP concentrations and impaired phagocytosis suggesting that fatty acids must first go through a cycle of esterification and re-hydrolysis before they are available as energy substrate. Exogenously added glucose cannot fully compensate for the phagocytotic defect in Atgl(-/-) macrophages. Hence, phagocytosis was also decreased in vivo when Atgl(-/-) mice were challenged with bacterial particles. These findings imply that phagocytosis in macrophages depends on the availability of FFAs and that ATGL is required for their hydrolytic release from cellular TG stores. This novel mechanism links ATGL-mediated lipolysis to macrophage function in host defense and opens the way to explore possible roles of ATGL in immune response, inflammation, and atherosclerosis.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria.
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.forename: Elma
authors.initials: E
authors.lastname: Aflaki
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.forename: Marlene
authors.initials: M
authors.lastname: Buchebner
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004926:Escherichia coli / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000493:pharmacokinetics; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D050259:Genes, Mitochondrial / Q000235:genetics; D006801:Humans; D006868:Hydrolysis; D008049:Lipase; D050356:Lipid Metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010587:Phagocytosis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002265:Carboxylic Ester Hydrolases; D005230:Fatty Acids, Nonesterified; D008049:Lipase; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases