Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Buchebner, M.
The role of Hormone-sensitive Lipase and KIAA1363 in lipid metabolism of mouse peritoneal macrophages.
[ Dissertation ] Graz Medical University ; 2009. pp.140.
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Buchebner Marlene
- Betreuer*innen:
- Kostner Gerhard
- Kratky Dagmar
- Altmetrics:
- Abstract:
- Atherosclerosis is the most common cause for stroke and cardiovascular disease in westernized societies. Different cell types including monocytes, smooth muscle cells and macrophages play a central role in this multifactorial disease. Macrophages are able to take up modified low density lipoprotein via scavenger receptors and store tremendous amounts of cholesteryl esters (CE) in lipid droplets leading to foam cell formation, which is one of the earliest and important step in the initiation and progression of atherosclerosis. Foam cells are able to mobilize massive lipid deposition by the action of a neutral CE hydrolase. Due to the importance of this enzyme activity in macrophages and conflicting publications over 40 years I compared the lipolytic activities of two suggested neutral CE hydrolases in mouse peritoneal macrophages: hormone-sensitive lipase (HSL) and KIAA1363. First I determined the gene expression profiles of these two genes in several mouse tissues and cells in regard to any sex-specific differences in macrophages and foam cells by quantitative real time PCR. Furthermore, the enzyme activities against CE, triglycerides, diglycerides and acetyl monoalkylglycerol ether (AcMAGE) in COS-7 cells overexpressing HSL and KIAA1363 were investigated. Whereas HSL cleaved all substrates, KIAA1363 was only able to hydrolyze AcMAGE in vitro. For in vivo studies, HSL- deficient and KIAA1363- deficient mice were used. I found nearly abolished neutral CE hydrolase activity in all cells and tissues of HSL-deficient mice and reduced AcMAGE hydrolase activities in macrophages and some tissues of KIAA1363- deficient mice. Moreover, I could show that HSL is localized in the cytosol and next to lipid droplets. In macrophages KIAA1363 gene expression is influenced by lipopolysaccharide stimulation. The results demonstrate the functional presence of HSL as a neutral CE hydrolase in murine macrophages but, due to the unchanged lipid content in macrophages of HSL- deficient mice, another mechanism, other compartments and/or other enzymes cooperate with HSL to regulate CE levels in macrophages in vivo. In contrast, KIAA1363 might be an important AcMAGE hydrolase in MPM, but does not hydrolize CE in vitro or in vivo.