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.

Lipin-1 Integrates Lipid Synthesis with Proinflammatory Responses during TLR Activation in Macrophages

“…LPS-treated cells display a very robust membrane rearrangement (25,26); hence they require a high energy supply to accomplish all the remodeling that activation encompasses, including the upregulation of many genes and proteins. In fact, TAG production is increased in activated macrophages (6,(27)(28)(29), and its hydrolysis is an absolute requirement for efficient ATP supply and macrophage functioning (30). Thus, the possibility exists that in the absence of lipin-1 macrophages may not be able to meet the necessary energy levels to fulfill all their activation requirements, resulting in alteration of the whole cell reprograming.…”

Macrophage lipoprotein lipase modulates the development of atherosclerosis but not adiposity

“…Macrophage phagocytosis demands a large amount of ATP and plays an essential role in host defense. Chandak et al have recently reported that a defi ciency in adipose triglyceride lipase, a rate limiting enzyme involved in the hydrolysis of lipid dropletassociated TG, in macrophages resulted in a decrease in CPT-1 expression and impaired phagocytosis ( 42 ). Others have also previously reported that macrophage LpL acts on TG-rich lipoproteins to produce FA, which is an important source of energy for phagocytosis ( 43 ).…”

AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue

“…FAs or their derivatives, as a ligand, can bind and activate the nuclear receptor family of transcription factors, PPARs. Desnutrin/ATGL-deficient mice with impaired lipolysis exhibited a severe defect in PPAR␣ signaling in oxidative tissues such as BAT (15), liver (54), macrophages (55), and cardiac muscle (56). In addition, adipose-tissue-specific overexpression of PPAR␦ in mice has been shown to enhance the expression of genes for FA oxidation (57).…”