Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase.
Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase.
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DOI：
10.1074/jbc.m110.107854
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发表时间：
2010-06-25
期刊：
影响因子：
--
通讯作者：
Kratky D
中科院分区：
文献类型：
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作者：
Chandak PG;Radovic B;Aflaki E;Kolb D;Buchebner M;Fröhlich E;Magnes C;Sinner F;Haemmerle G;Zechner R;Tabas I;Levak-Frank S;Kratky D
巨噬细胞的吞噬作用是宿主防御的重要生物学过程，需要大量的能量。迄今为止，葡萄糖被认为是巨噬细胞中ATP产生的主要底物。为了研究游离脂肪酸（FFA）在这一过程中的相对贡献，我们测定了正常小鼠巨噬细胞和脂肪甘油三酯脂肪酶（ATGL）缺陷小鼠巨噬细胞的吞噬率。ATGL是许多组织中脂滴相关三酰甘油（TG）水解的限速酶。在这里，我们证明了Atgl−/−巨噬细胞不能有效地水解细胞TG储存，导致细胞FFA浓度降低和伴随的脂滴积累，即使在没有外源性脂质负荷的情况下。FFA的可用性降低导致细胞ATP浓度降低和吞噬作用受损，这表明脂肪酸在可用作能量底物之前必须首先经历酯化和再水解的循环。外源性葡萄糖不能完全弥补Atgl−/−巨噬细胞的吞噬缺陷。因此，当Atgl−/−小鼠受到细菌颗粒攻击时，体内吞噬作用也会降低。这些发现意味着巨噬细胞中的吞噬作用取决于FFA的可用性，并且ATGL是其从细胞TG储存中水解释放所需的。这种新的机制将ATGL介导的脂解作用与宿主防御中的巨噬细胞功能联系起来，并为探索ATGL在免疫反应、炎症和动脉粥样硬化中的可能作用开辟了道路。
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.