Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schlager, S.
The Role of Intracellular Neutral Lipid Hydrolases in Immune Cell Function
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2015. pp.
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- Autor*innen der Med Uni Graz:
- Schlager Stefanie
- Betreuer*innen:
- Kratky Dagmar
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- Abstract:
- Lipid droplets (LDs) are cytoplasmic organelles in immune cells with an important role in the development of metabolic diseases and inflammation. LD accumulation in macrophages is a recognized early event in atherogenesis and leads to the formation of “fatty streaks” representing initial atherosclerotic lesions. Under certain inflammatory conditions also other immune cells (e.g. leukocytes) generate cytosolic, triglyceride (TG)-rich LDs, which are considered as key markers of cellular activation. To date, the lipolytic enzymes involved in maintaining LD homeostasis in these cells have not been defined. The first part of this thesis clearly shows that the TG-hydrolyzing enzymes adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL) are regulators of LD metabolism in immune cells, thereby regulating immune cell biology and function. With specific emphasis on ATGL, which is the rate-limiting enzyme mediating TG hydrolysis, I observed an increased abundance of intracellular, TG-rich LDs in neutrophil granulocytes similar to humans with loss-of-function mutations in ATGL. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl-/- mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl-/- mice. Mechanistically, ATGL deficiency and pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. In the second part of my thesis I aimed at investigating the impact of the deficiency of the lipolytic enzymes ATGL, HSL, and MGL on platelet function. Thereby I observed that the absence of ATGL and MGL but not HSL was associated with an anti-thrombogenic phenotype, as evident by reduced in vitro thrombogenesis and collagen-induced platelet activation. In summary, the present work provides profound evidence for a functional role of TG- hydrolyzing enzymes in the regulation of LD metabolism in immune cells. These observations expand the knowledge of these enzymes as signaling lipases and potent regulators of immune cell function and inflammatory diseases. Uncovering these lipid regulatory pathways may identify new pharmacological targets to regulate the inflammatory activity of immune cells.