Medizinische Universität Graz - Research portal
Selected Publication:
Chandak, P.
Role of adipose triglyceride lipase in macrophage function and its impact on atherosclerosis
[ Dissertation ] Medical University of Graz; 2010. pp. 104
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- Authors Med Uni Graz:
- Chandak Prakash Gopal Das
- Advisor:
- Kratky Dagmar
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- Abstract:
- Adipose triglyceride lipase (Atgl) was shown to be the rate-limiting enzyme for the hydrolysis of lipid droplet-associated triglycerides (TG) in many tissues. Atgl-/- macrophages fail to efficiently hydrolyze cellular TG stores leading to decreased cellular free fatty acid (FFA) concentrations. This leads to concomitant accumulation of lipid droplets in Atgl-/- macrophages even in the absence of exogenous lipid loading. Macrophage phagocytosis is an essential biological process in host defense and requires large amounts of energy. The reduced availability of FFAs results in decreased cellular ATP concentrations in Atgl-/- macrophages. Phagocytosis was reduced in Atgl-/- macrophages compared to WT macrophages. 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. Impaired phagocytosis in Atgl-/- macrophages suggests that FAs must first go through a cycle of esterification and re-hydrolysis before they are available as energy substrate. 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. The role of cholesterol in atherogenesis is well studied, but the effect of TG accumulation in macrophages and its impact on atherogenesis has not been explored. Therefore, low-density lipoprotein receptor knockout (Ldlr-/-) mice were transplanted with bone marrows from Atgl-/- mice (Atgl-/- ¿ Ldlr-/-) or wild-type mice (WT ¿ Ldlr-/-) and challenged with Western-type diet for 9 weeks to induce atherosclerosis. Despite increased lipid accumulation in Atgl-/- macrophages, atherosclerosis in Atgl-/- ¿ Ldlr-/- mice was 43 % reduced. This coincided with increased intraplaque apoptosis and reduced macrophages infiltration in the arterial walls. Plasma macrophage-chemoattractant protein 1 (MCP-1) concentrations and total number of white blood cells were decreased Atgl-/- ¿ Ldlr-/- mice. We conclude that the attenuation of atherogenesis in Atgl-/- ¿ Ldlr-/- mice is due to decreased infiltration of less inflammatory macrophages into the arterial walls and increased intraplaque apoptosis. Atgl inhibition in macrophages might be a good target to inhibit early lesion formation.