Modified LDL in the Pathogenesis of Atherosclerosis: Role of Nutrition

Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs.

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Abstract 1455: Athero-protective Role of IL10 Involves Regulation of Lipid Metabolism in Macrophages

Circulation ◽

10.1161/circ.116.suppl_16.ii_299-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Xinbing Han ◽

Shiro Kitamoto ◽

Qingyu Lian ◽

William A Boisvert

Keyword(s):

Lipid Metabolism ◽

Cholesterol Efflux ◽

Foam Cell ◽

Foam Cells ◽

Foam Cell Formation ◽

Lipid Uptake ◽

Modified Ldl ◽

Ldl Uptake ◽

Inflammatory Molecules

Introduction Previous studies utilizing interleukin (IL)10-overexpressing mice and IL10-deficient mice have demonstrated an anti-atherogenic role of IL10. Internalization of modified low density lipoprotein (LDL) that leads to foam cell formation has long been considered one of the requisite initiating events in atherogenesis. We sought to determine if IL10 exerts its anti-atherogenic effect by modulating lipid metabolism in the macrophage. Methods & results In lipid uptake studies, IL10 substantially stimulated Dil-acetylated (Ac)LDL uptake by 187% in murine macrophage-like RAW264.7 cells. IL10 induced the expression of SR-AII and CD36 by 15.1 fold and 6.5 fold, respectively, in macrophage-derived foam cells. Moreover, CD36 protein levels were increased by IL10, suggesting that these scavenger receptors account, at least in part, for the increase in modified LDL uptake by the macrophages. Accordingly, IL10 treatment for 24hr significantly increased cholesteryl ester content by 1.5 folds compared with untreated controls (p<0.05). Interestingly, IL10 also markedly promoted ATP-binding cassette protein A1 (ABCA1)-mediated free cholesterol efflux to lipid-free apoAI acting as a cholesterol acceptor. This was peroxisome proliferator-activated receptor (PPAR)γ-dependent because specific PPARγ antagonist GW9226 completely blocked the IL10-triggered cholesterol efflux to lipid-free apoAI. In addition, expression of pro-inflammatory molecules such as TNFα, MCP-1 and iCAM-1 was dramatically inhibited by IL10 in the lipid-laden foam cells. Using immunofluorescence assay of caspase 3 fragment and TUNEL assay, we demonstrated that IL10 significantly suppressed apoptosis of foam cells (27.3 ± 2.1% for AcLDL-treated cells vs. 8.3 ± 1.0 %for AcLDL plus IL10-treated cells, n=8). Conclusion Our results indicate that IL10 can mediate both the uptake of cholesterol from modified LDL and the efflux of stored cholesterol. Therefore, IL10 may facilitate the removal of harmful atherogenic lipoprotein molecules from the vessel wall. These characteristics along with its ability to suppress the expression of inflammatory molecules and apoptosis of foam cells make IL10 a highly anti-atherogenic agent.

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