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Review
. 2012 Mar;1821(3):513-21.
doi: 10.1016/j.bbalip.2011.08.003. Epub 2011 Aug 16.

Anti-atherogenic mechanisms of high density lipoprotein: effects on myeloid cells

Andrew J Murphy  1 , Marit Westerterp, Laurent Yvan-Charvet, Alan R Tall
Affiliations
Review

Anti-atherogenic mechanisms of high density lipoprotein: effects on myeloid cells

Andrew J Murphy et al. Biochim Biophys Acta. 2012 Mar.

Abstract

In some settings increasing high density lipoprotein (HDL) levels has been associated with a reduction in experimental atherosclerosis. This has been most clearly seen in apolipoprotein A-I (apoA-I) transgenic mice or in animals infused with HDL or its apolipoproteins. A major mechanism by which these treatments are thought to delay progression or cause regression of atherosclerosis is by promoting efflux of cholesterol from macrophage foam cells. In addition, HDL has been described as having anti-inflammatory and other beneficial effects. Some recent research has linked anti-inflammatory effects to cholesterol efflux pathways but likely multiple mechanisms are involved. Macrophage cholesterol efflux may have a role in facilitating emigration of macrophages from lesions during regression. While macrophages can mediate cholesterol efflux by several pathways, studies in knockout mice or cells point to the importance of active efflux mediated by ATP binding cassette transporter (ABC) A1 and G1. In addition to traditional roles in macrophages, these transporters have been implicated in the control of hematopoietic stem cell proliferation, monocytosis and neutrophilia, as well as activation of monocytes and neutrophils. Thus, HDL and cholesterol efflux pathways may have important anti-atherogenic effects at all stages of the myeloid cell/monocyte/dendritic cell/macrophage lifecycle. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

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Figures

Figure 1
Figure 1. Anti-atherogenic functions of HDL - sites of action
A) HDL interacts with ABCA1 and ABCG1 on the HSPCs to promote cholesterol efflux and inhibit their proliferation. This regulates the number of mature myeloid cells produced. B,C) HDL and apoA-I can act as an anti-inflammatory reducing monocyte and neutrophil activation. This leads to less recruitment of monocytes/neutrophils to the atherosclerotic lesion. D) HDL interacts with macrophages to regulate a number of cellular functions important to controlling atherosclerosis such as cholesterol efflux, reducing TLR-4 signaling, decreasing apoptosis during efferocytosis and modulating membrane lipid levels to aid in macrophage migration.
Figure 2
Figure 2. The importance of cholesterol efflux in regulating HSPC proliferation and myelopoiesis
A) Under normal conditions HSPCs utilize ABCA1 and ABCG1 to efflux cholesterol to apoA-I/HDL and ApoE. This controls the amount of cholesterol in the cell membrane (lipid rafts) and may also ensure correct expression of proliferative cytokine receptors including IL-3Rβ. B) When cholesterol efflux pathways are disrupted the abundance of lipid rafts in the membrane of the HSPCs increases causing an increase in the expression of the IL-3Rβ. This results in the HSPC becoming more sensitive to cytokine induced proliferation and the pool of HSPCs begins to proliferate and expand. This ultimately causes enhanced myelopoiesis, more blood monocytes and this likely has an effect of accelerating atherosclerosis. C=cholesterol.
Figure 3
Figure 3. Anti-inflammatory functions of HDL on the macrophage
ABCA1 and ABCG1 promote cholesterol efflux from macrophages to apoA-I/HDL. This interaction can attenuate macrophage inflammation via a number of pathways. A) The removal of cholesterol from lipid rafts can decrease TLR-4/CD14 expression on the surface of the macrophage desensitizing signaling by LPS. B) HDL can inhibit LPS stimulated type I INF response independent of sterol metabolism via a mechanism involving removal of the TRAM signaling molecule away from the cell membrane and into intracellular compartments. C) Binding of apoA-I to ABCA1 causes the activation of JAK-2 which then allows STAT-3 to directly bind and become activated by ABCA1. This results in the transcription of TTP which targets and degrades the inflammatory mRNAs transcribed by NF-κB from LPS signaling. C=Cholesterol
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