Results from studies investigating the effect of inflammation on steps in the reverse cholesterol transport pathway have been conflicting. In addition, HDL remodelling during inflammation generates an abundance of triglycerides and a loss of HDL-associated proteins such as apoA-II, CETP, LCAT, PAF-AH, and PON. Increased oxidative stress during inflammation generates HDL that contains oxidatively modified apoA-I. Inflammatory cytokines induce the hepatic expression of acute-phase SAA and group IIa sPLA 2, which leads to the formation of HDL particles that are relatively enriched in SAA and depleted of apoA-I and phospholipid. HDL undergoes substantial modification during an acute-phase response. Abbreviations: ABCA1, ATP-binding cassette transporter A1 ABCG1, ATP-binding cassette transporter G1 apoA-I, apolipoprotein A-I apoB-100, apolipoprotein B-100 CE, cholesteryl ester HDL, high-density lipoprotein HDL-L, large HDL particle HDL-S, small HDL particle HDL-VL, very large HDL particle HDL-VS, very small HDL particle ICAM1, intercellular adhesion molecular 1 LCAT, lecithin-cholesterol acetyltransferase LDL, low-density lipoprotein NO, nitric oxide VCAM1, vascular cell adhesion protein 1. HDL also enhances the endothelial synthesis of NO, a potent vasodilator, to ameliorate endothelial dysfunction, and might also reduce coronary atherosclerosis by decreasing the expression of adhesion molecules on endothelial cells to reduce inflammation, and by decreasing LDL oxidation.
LCAT catalyses the esterification of cholesterol to CEs and the maturation of HDL to CE-rich mature HDL, which can transport cholesterol back to the liver or exchange CEs for triglycerides with the apolipoprotein B-containing lipoproteins. In reverse cholesterol transport, preβ-HDL (HDL-VS) binds to the ABCA1 transporter and initiates cholesterol efflux with the conversion of preβ-HDL (HDL-VS) to HDLα (HDL-S). HDL performs a pivotal role in removing cholesterol from cholesterol-loaded macrophages by binding to ABCA1 and stimulating the process of reverse cholesterol transport. HDL protects against atherosclerosis through multiple mechanisms, as illustrated. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport.
7 INSERM-ICAN Research Unit 1166 of the National Institute for Health and Medical Research at Pitié-Salpétrière University Hospital, Paris, France.6 Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA.5 National Institute for Health and Medical Research at Pitié-Salpétrière University Hospital, Paris, France.4 Centre for Vascular Research at the University of New South Wales, Sydney, Australia.3 Cardiology Department, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.2 Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA.1 Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.