New roles of HDL in inflammation and hematopoiesis - PubMed (original) (raw)

Review

New roles of HDL in inflammation and hematopoiesis

Xuewei Zhu et al. Annu Rev Nutr. 2012.

Abstract

High-density lipoprotein (HDL) levels are inversely associated with coronary heart disease due to HDL's ability to transport excess cholesterol in arterial macrophages to the liver for excretion [i.e., reverse cholesterol transport (RCT)]. However, recent advances highlight additional atheroprotective roles for HDL beyond bulk cholesterol removal from cells through RCT. By promoting cellular free cholesterol (FC) efflux, HDL and its apolipoproteins (apoA-I and apoE) decrease plasma membrane FC and lipid raft content in immune and hematopoietic stem cells, decreasing inflammatory and cell proliferation signaling pathways. HDL and apoA-I also dampen inflammatory signaling pathways independent of cellular FC efflux. In addition, HDL lipid and protein cargo provide protection against parasitic and bacterial infection, endothelial damage, and oxidant toxicity. Here, current knowledge is reviewed regarding the role of HDL and its apolipoproteins in regulating cellular cholesterol homeostasis, highlighting recent advances on novel functions and mechanisms by which HDLs regulate inflammation and hematopoiesis.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Reverse cholesterol transport (RCT). Excess cellular free cholesterol (FC) can be esterified by acyl CoA:cholesterol acyltransferase (ACAT), forming a cholesteryl ester (CE) cytosolic lipid droplet. CE can be mobilized into FC by cholesterol ester hydrolase (CEH) for transport to the plasma membrane. Excess FC in peripheral tissues, including arterial macrophages, is transported out of cells to high-density lipoproteins (nascent HDL and plasma HDL) via passive diffusion or by a transporter-mediated active lipid efflux involving ABCA1, ABCG1, and/or SR-BI. LCAT converts FC to CE in HDL particles. HDL FC and CE are taken up in the liver by the hepatic scavenger receptor (SR-BI) or transferred to apoB-containing lipoproteins by cholesterol ester transfer protein (CETP) with subsequent uptake by hepatic low-density lipoprotein (LDL) receptors (LDLr). Hepatic FC can be directly secreted into the bile via ABCG5/G8 or converted to bile acids (BA) before secretion into bile. Cholesterol in secreted bile mixes with dietary cholesterol and is available for absorption into intestinal enterocytes by Niemann-Pick C1-like 1 (NPC1L1) protein. Absorbed cholesterol can be transported back into the intestinal lumen by ABCG5/G8. A poorly defined trans-intestinal transport and excretion (TICE) pathway bypasses the liver and delivers excess plasma cholesterol by an unknown lipoprotein into the intestinal lumen. The final step in RCT is the ultimate excretion of cholesterol in the feces. The net result of these RCT pathways is decreased accumulation of excess cellular cholesterol.

Figure 2

Figure 2

Regulation of intracellular cholesterol homeostasis. Cellular cholesterol content is normally tightly regulated by balancing uptake and endogenous synthesis with efflux and storage. Cholesterol in lipoproteins is internalized via scavenger receptors (CD36, SR-A) or low-density lipoprotein receptors (LDLr) and delivered to endosomes where cholesteryl ester (CE) is hydrolyzed to free cholesterol (FC). Niemann-Pick C1 (NPC1) together with NPC2 regulates FC movement out of the endosomes for delivery to the endoplasmic reticulum (ER) or the plasma membrane. Excess FC in the ER can be esterified to CE by acyl CoA:cholesterol acyltransferase (ACAT), forming a cytosolic lipid droplet. CE can be mobilized from the lipid droplet by cholesterol ester hydrolase (CEH) for transport to the plasma membrane. When cellular cholesterol level is low, sterol regulatory element-binding protein 2 (SREBP2) is escorted by SREBP cleavage-activating protein (SCAP) from the ER to the Golgi, where it undergoes cleavage by site 1 and site 2 proteases (S1P and S2P). The proteolytic processing of SREBP2 releases the N-terminus, which is a basic helix-loop-helix leucine zipper transcription factor that travels to the nucleus to activate transcription of genes involved in cholesterol biosynthesis and cholesterol uptake (i.e., LDLr). A minor amount of FC can be oxidized into oxysterol, an activating ligand for liver X receptors (LXRs), resulting in increased transcription of cholesterol efflux genes (i.e., ABCA1, ABCG1, and apoE) and Idol (inducible degrader of LDLr), which mediates degradation of the LDLr. FC transported to the plasma membrane can be effluxed to lipid-free apolipoproteins (i.e., apoA-I and apoE) by ABCA1 or to high-density lipoprotein (HDL) particles by passive diffusion or transporters (ABCG1 or SR-BI). Modified from (31).

Figure 3

Figure 3

Summary of roles of high-density lipoprotein (HDL), apolipoproteins, and ABC transporters in regulating inflammatory response and hematopoietic stem cell proliferation. Lipid-poor apoA-I or cell surface proteoglycan-bound apolipoprotein (apo)E stimulates free cholesterol (FC) and phospholipid (PL) efflux from macrophages or hematopoietic stem cells via ATP-binding cassette transporter (ABC) A1 to form nascent HDL (nHDL) particles. nHDL or plasma HDL can efflux additional FC and PL from the cells via ABCG1, forming FC-enriched nHDL and plasma HDL, thereby reducing cellular cholesterol levels. The reduction in membrane FC content mediated by ABCA1 and ABCG1 efflux results in reduced membrane lipid raft content. This, in turn, reduces inflammatory and proliferative pathways by reducing Toll-like receptor (TLR) 4 receptor and the common beta subunit of the interleukin (IL)-3/granulocyte macrophage colony-stimulating factor (GM-CSF) receptor (IL-3Rβ) in lipid rafts on the macrophage and hematopoietic stem cell surface, respectively. HDL also inhibits lipopolysaccharide (LPS)-stimulated type I interferon response in macrophages by inducing sequestration of TLR4 adapter TRIF-related adapter molecule (TRAM) in an intracellular compartment in a sterol-independent manner. Interaction of apoA-I with ABCA1 activates Janus kinase 2/signal transducer and activator of transcription 3 ( JAK2/STAT3) and increases transcription of tristetraprolin (TTP), resulting in destabilization of microRNAs of proinflammatory genes. Modified from (61, 64).

Similar articles

Cited by

References

    1. Alwaili K, Bailey D, Awan Z, Bailey SD, Ruel I, et al. The HDL proteome in acute coronary syndromes shifts to an inflammatory profile. Biochim. Biophys. Acta. 2011;1721:405–15. - PubMed
    1. Angeli V, Llodra J, Rong JX, Satoh K, Ishii S, et al. Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity. 2004;21:561–74. - PubMed
    1. Armstrong AJ, Gebre AK, Parks JS, Hedrick CC. ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation. J. Immunol. 2010;184:173–83. - PMC - PubMed
    1. Attie AD, Kastelein JP, Hayden MR. Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J. Lipid Res. 2001;42:1717–26. - PubMed
    1. Baldan A, Gomes AV, Ping P, Edwards PA. Loss of ABCG1 results in chronic pulmonary inflammation. J. Immunol. 2008;180:3560–68. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources