Atherosclerosis is a chronic inflammatory disease of the arteries that represents the root cause of the majority of heart attacks and strokes. The accumulation of lipid droplets (LDs) in macrophages and their subsequent transformation into foam cells is one of the key steps in the development of atherosclerotic lesions. It has been traditionally thought that this process is largely dependent on the accumulation of oxidised low-density lipoprotein (OxLDL) via uptake by macrophage scavenger receptors. However, as DNA signatures from a wide array of bacterial species have been identified in human atherosclerotic lesions, this project aimed to investigate whether and by which mechanisms these organisms may modulate macrophage foam cell formation, with a particular emphasis on the potential roles played by Toll-like receptor (TLR) signalling. The present findings establish that exposure of murine or human macrophages to diverse heat-killed atheroma-associated bacteria, or stimulants of any TLR, leads to the accumulation of cholesterol ester and foam cell formation. This process is dependent on TLR signalling, particularly TLR2 and TLR4, but independent of lipoprotein oxidation or scavenger receptor uptake, and although it is dose-dependently potentiated by LDL, it can also occur in the absence of LDL supplementation. TLR-dependent lipid accumulation is not due to enhanced pinocytosis or LDL receptor-dependent LDL uptake. Instead, the results indicate both reduced cholesterol efflux to HDL and increased de novo lipid synthesis, via TLR-dependent modulation of key proteins of the two pathways, the ABCA1/G1 cholesterol efflux proteins, and 3-hydroxy-3-methylglutatyl CoA reductase (HMGCR), respectively. Taken together, the results point towards a novel mechanism of foam cell formation that begins in circulating monocytes exposed to bacteria or their products before they are recruited to developing lesions. Novel therapies for the prevention of atherosclerosis could be developed to target the mechanisms of crosstalk between the TLR and lipid regulatory pathways identified by the current project.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:593729 |
| Date | January 2013 |
| Creators | Nicolaou, Giovanna |
| Contributors | Erridge, Clett; Goodall, Alison H. |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/28530 |
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