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Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin.


ABSTRACT: Atherosclerosis is characterized as a chronic inflammatory condition that involves cholesterol deposition in arteries. Together with scavenger receptor B1 (SR-B1), the ATP-binding cassette transporters ABCA1 and ABCG1 are the major components of macrophage cholesterol efflux. Recent studies have shown that low-grade inflammation plays a distinct regulatory role in the expression of SR-B1 and ABCA1/ABCG1. However, the mechanisms linking low-grade inflammation and cholesterol accumulation are poorly understood.Using primary bone-marrow-derived macrophages, we demonstrate that subclinical low-dose lipopolysaccharide potently reduces the expression of SR-B1 and ABCA1/ABCG1, as well as cholesterol efflux from macrophages through interleukin-1 receptor-associated kinase 1 and Toll-interacting-protein. Low-dose lipopolysaccharide downregulates the nuclear levels of retinoic acid receptor-?, leading to their reduced binding to the promoters of SR-B1 and ABCA1/ABCG1. We observe that glycogen synthase kinase 3? activation by low-dose lipopolysaccharide through interleukin-1 receptor-associated kinase 1 and Toll-interacting-protein is responsible for reduced levels of retinoic acid receptor-?, and reduced expression of SR-B1 and ABCA1/ABCG1. Interleukin-1 receptor-associated kinase M, however, counteracts the function of interleukin-1 receptor associated kinase 1.Collectively, our data reveal a novel intracellular network regulated by low-dose endotoxemia that disrupts cholesterol efflux from macrophages and leads to the pathogenesis of atherosclerosis.

PROVIDER: S-EPMC3545450 | BioStudies |

REPOSITORIES: biostudies

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