Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase.
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.
Chandak
Prakash G
PG
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria.
Radovic
Branislav
B
Aflaki
Elma
E
Kolb
Dagmar
D
Buchebner
Marlene
M
Fröhlich
Eleonore
E
Magnes
Christoph
C
Sinner
Frank
F
Haemmerle
Guenter
G
Zechner
Rudolf
R
Tabas
Ira
I
Levak-Frank
Sanja
S
Kratky
Dagmar
D
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
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002265:Carboxylic Ester Hydrolases; D005230:Fatty Acids, Nonesterified; D008049:Lipase; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases