Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Doddapattar, P.
Targeting atherosclerosis: chemical, genetic and proteomic approaches
[ Dissertation ] Medical University of Graz; 2013. pp. 121
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- Autor*innen der Med Uni Graz:
- Doddapattar Prakash
- Betreuer*innen:
- Kostner Gerhard
- Kratky Dagmar
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- Abstract:
- Accumulation of cholesterol and other lipids in the arteries constitute most prominent manifestation of atherosclerosis. In addition to lipid build up, circulating inflammatory markers fuel the disease condition. To counter-balance variations in physiology, metabolic and immune responses play a very basic role in homeostasis of multicellular organisms. Xanthohumol (XN) is a prenylated anti-oxidative and anti-inflammatory compound with positive effects on lipid and glucose metabolism. Herein, we demonstrate a role of XN as a potent lipid lowering compound, down-regulating inflammation and thereby reducing atherosclerosis. In addition to improving hypercholesterolemia, oral supplementation of XN leads to phosphorylation/activation of AMPK and its downstream target acetyl-CoA carboxylase leading to reduced hepatic lipid accumulation in Apolipoprotein E-deficient (ApoE(-/-)) mice. Likewise, XN feeding down-regulated protein expression of mature SREBP-2 and reduced transcriptional expression of SREBP-1c and its well-known target stearoyl-CoA desaturase 1. Concomitant induction of hepatic mRNA expression of carnitine palmitoyltransferase-1a in ApoE-/- mice administered with XN suggests increased fatty acid beta-oxidation. Fecal cholesterol concentrations were also markedly increased in XN-fed ApoE-/- mice compared with mice fed western-type diet alone. Our work reveals potential action of XN as atheroprotective compound, improving hypercholesterolemia, inflammation and hepatic steatosis. Therefore XN may constitute a therapeutic compound for the treatment of atherosclerosis. PLIN1 is the most abundant protein associated with lipid droplet (LD)s of many cell types. LD-rich macrophage-derived foam cells are a defining feature of atherosclerotic plaque development. Increased expression of PLIN1 during differentiation of human 8 monocytes to macrophages prompted us to study the role of PLIN1 in foam cell formation and atherosclerosis. We show that Plin1 inactivation in ApoE-/- (ApoE-/-Plin1-/-) mice reduced accumulation of LDs in macrophage-derived foam cells and protected mice against atherosclerosis. Mechanistically, decreased atherosclerosis in ApoE-/-Plin1-/- mice might be the result of increased cholesterol efflux and low levels of circulating triglyceride concentrations in the plasma and the ability of macrophages to maintain reduced foam cell formation. We further show that whole body deletion of Plin1 (Plin1-/-) in mice results in the increased macrophage cell spreading. In conclusion, Plin1 deletion in ApoE-/- mice protects against atherosclerosis and therefore inhibition of PLIN1 might be atheroprotective. The structural proteins and hydrolases on lipid droplets (LDs) of macrophage-derived foam cells have a regulatory role in lipid storage and release. PERILIPINs constitute the most abundant structural proteins on LDs. In order to gain insight into the distribution of proteins that govern the flux of lipids into/from LDs, we studied protein composition in macrophage LDs. Since we have found reduced atherosclerosis and decreased number of foam cells in an atherosclerotic mouse model lacking perilipin1 (Plin1), we were interested in differences in LD-associated proteins of wild type (Wt) and Plin1-deficient (-/-) foam cells. Foam cell formation was induced by incubating peritoneal macrophages in the presence of acetylated low density lipoprotein (acLDL). LDs were purified by density gradient centrifugation; the LD proteomes were compared by LC-MS/MS after isotopic labelling of peptides. We found a number of LD-associated proteins both that are known to be expressed on LDs and some of unknown functions. Among many differentially expressed proteins, we found reduced expression of ATGL, CGI-58 and Rab18 on the LDs of Plin1-/- compared to Wt macrophages.