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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.

SUBMITTER: Maitra U

PROVIDER: S-EPMC3545450 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Maitra Urmila U Li Liwu L

Arteriosclerosis, thrombosis, and vascular biology 20121101 1

<h4>Objective</h4>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 acc ...[more]

PMID: 23117655

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Project description:FcgRIIB dysfunction is commonly found in patients with lupus, especially in Asia. LPS-tolerance is prominent in FcgRIIB-/- lupus mice. LPS-tolerant macrophages demonstrate cell energy depletion, which might affect lipid metabolism. Therefore, to explore lipid metabolism, LPS-tolerance was induced twice by LPS administration in macrophages and in mice. LPS-tolerant FcgRIIB-/- macrophages demonstrated lesser mitochondrial DNA (mtDNA), more severe ATP depletion, lower cytokine production, and higher lipid accumulation (oil red O staining) compared to LPS-tolerant WT cells. Mass-spectrometry-based lipidomic analysis demonstrated a higher abundance of phosphatidylethanolamine (PE) phospholipid in LPS-tolerant FcgRIIB-/- macrophages than WT cells. This was at least in part due to the lower expression of phosphatidylethanolamine N-methyltransferase (pemt), an enzyme that converts PE to phosphatidylcholine (PC). Aminoimidazole-4-carboxamide ribonucleotide (AICAR), a pemt inhibitor, worsens LPS-tolerance in WT macrophages and supports the impact of pemt upon LPS-tolerant FcgRIIB-/- macrophages. Additionally, phosphorylated AMP-activated protein kinase (AMPK-p), a molecule for ATP-restoration associated with pemt, and phosphorylated acetyl CoA carboxylase, a downstream signaling of AMPK-p, were higher in LPS-tolerant FcgRIIB-/- macrophages than WT. Furthermore, Compound C, an AMPK inhibitor, attenuated LPS-tolerance in both FcgRIIB-/- macrophages and mice. Taken together, the intense decrease in cytokine production after the second LPS stimulation (LPS-tolerance) in FcgRIIB-/- macrophages was possibly due to the impact of an immense cytokine synthesis after the first dose of LPS. This includes using up PEMT, an enzyme of phospholipid synthesis during cytokine production, and AMPK-p induction in response to profound ATP-depletion. Therefore, the manipulation of the AMPK/PEMT axis provides a novel therapeutic candidate for the treatment of severe LPS-tolerance in lupus.

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

Publications

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

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