Managing Residual CVD Risk: The Role of HDL Cholesterol – Issue 2

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Issue Author
Benjamin J. Ansell, MD FACC, FACP, FNLA
Professor of Medicine
UCLA School of Medicine
Divisions of General Internal Medicine and Cardiology
Los Angeles, CA

Series Chair
Clinical Professor
University of Illinois
School of Medicine
Peoria, IL
Director of Preventive Cardiology
Sterling Rock Falls Clinic, Ltd.
Sterling, IL

Click Here to read Dr. Tóth’s commentary on this issue.



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Issue 2: HDL and Atherogenesis


Introduction: HDL Structure, Composition, and Function

High-density lipoproteins (HDLs) are amphipathic particles with a hydrophilic outer surface composed of phospholipid and a number of apolipoproteins, surrounding a core of lipid, including cholesterol.1 Although they have a strong relationship to atherogenesis, the HDLs likely evolved as part of the innate immune system.1 As such, in addition to containing multiple lipid-modifying enzymes, HDL particles normally contain larger numbers of proteins relating to complement regulation, inhibition of metalloproteinases, and regulation of the acute phase response.2

Among the lipid-regulating proteins, apolipoprotein A-1 (apoA-1) is the major apolipoprotein in HDL under most circumstances, and confers many of its atheroprotective effects. ApoA-1 is synthesized by intestinal and liver cells, and over its life cycle, adopts a specific conformation and associations with other peptides and lipids that appear to determine its functional capacity. Lipid-poor apoA-1 forms dimers that act as acceptors of free cholesterol (FC) from vascular wall macrophages via the lipid transporter ATP-binding membrane cassette transport protein A1 (ABCA1).1,3 ApoA-1 and the transferred lipid adopt a discoidal shape, and is referred to as pre-beta HDL, based upon its electrophoretic migration pattern (also called “nascent” HDL). FC is esterified to cholesteryl ester (CE) via the HDL-associated enzyme lecithin cholesteryl acyl transferase (LCAT), forming more mature “alpha” HDL.1 HDL enlarges in the process and acquires a spherical shape. Additional FC is transferred to HDL via another macrophage lipid transporter ABCG1 and esterified via LCAT.

This mature, cholesterol-enriched HDL can travel via the bloodstream and transfer its cholesterol to the liver for elimination as either FC or bile acids in bile, completing the process of reverse cholesterol transfer (RCT) through 1 of 2 pathways (Figure 1 ).4 Via the “direct” pathway, HDL can dock with scavenger receptor B-1 (SR-B1), transferring CE to hepatocytes. Alternatively, via the enzyme cholesteryl ester transfer protein (CETP), CE within HDL can be exchanged with triglycerides (TG) contained within apoB containing particles (such as low-density and very low-density lipoproteins, LDL and VLDL, respectively). In this “indirect pathway”, apoB-containing particles can dock with hepatic LDL-receptors and be taken up into hepatocytes.1


Figure 1. The role of HDL in reverse cholesterol transport.


ABCA1 = adenosine triphosphate-binding cassette-A1; A-I = apolipoprotein A-I; B = apolipoprotein B; CE = cholesterol ester; CETP = cholesteryl ester transfer protein; FC = free cholesterol; HDL = high-density lipoprotein; LCAT = lecithin cholesterol acyltransferase; LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor; SR-B1 = scavenger receptor B1; TG = triglycerides; VLDL = very low-density lipoprotein.

From: Davidson MH. J Am Coll Cardiol. 2011;57:1120-1121.
Used with permission.





The process of RCT is the best characterized of all HDL functions, and may help explain why HDL-cholesterol (HDL-C) concentration is a well-recognized inverse predictor of coronary heart disease (CHD) risk. However, this static measure of HDL-C content has its limitations in characterizing the effectiveness of HDL in promoting the dynamic, complex process of RCT.5 More recently, the ability of HDL to promote cholesterol efflux from macrophages has been shown to be a better (inverse) predictor of clinical risk than HDL-C.6 Furthermore, the HDL particle number as assessed by nuclear magnetic resonance (NMR) spectroscopy has been shown to be superior to HDL-C as a negative predictor of CHD.7 In patients with CHD, despite supranormal HDL-C levels, HDL has impaired ability to slow monocyte chemotaxis and lipid oxidation in vitro.8 In a case-control study, both of these measures discriminated CHD patients from healthy age- and sex-matched controls.8 Thus, factors other than the cholesterol content of HDL need to be considered in determining the relationship between this lipoprotein and risk for cardiovascular disease.

Under normal circumstances, HDL down-regulates macrophage/foam cell expression of monocyte chemotaxis protein-1 (MCP-1) and the expression of vascular endothelial cellular adhesion molecules.9 Both of these effects help to diminish the inflammatory response in the vascular wall. HDL also inhibits oxidation of LDL particles, which potentiate adhesion molecule and foam cell production. It may well be that reverse-cholesterol efflux is anti-inflammatory, in that HDL-induced efflux of oxidized lipids from within foam cells can help to remove this inflammatory stimulus.10 In addition, HDL has been shown to promote antiplatelet, antithrombotic, and endothelial functional effects and regulate systemic insulin sensitivity11 that may contribute to atheroprotection CHD.


Relationship Between Inflammation and HDL

While HDL plays multiple roles in moderating vascular inflammation, it also itself can become modified by systemic inflammation. In some cases, this results in oxidation or other chemical changes to HDL and/or its substituents. In other cases, the proteome and/or lipidome of HDL can be significantly impacted by conditions associated with oxidative stress and chronic inflammation. Examples of these include infection,12 autoimmune disease,13 diabetes mellitus,14 and chronic renal disease.15

HDL isolated from mice undergoes a dramatic change in composition and function following influenza infection. The HDL antioxidant enzymes paraoxonase and platelet-activating factor acetylhydrolase are reduced in activity, while levels of ceruloplasmin, and apolipoprotein J increase as part of this transformation (Figure 2).16 When assayed for its effect on in vitro assay of monocyte chemotaxis, the HDL from the infected mice exhibited paradoxical increase in the subendothelial influx of these inflammatory cells, thus providing evidence of a pro-inflammatory phenotype.16 In human survivors of sepsis, HDL is enriched in serum amyloid A and lacks apoA-1 compared with recovery levels of these proteins.17 Another study showed similar protein changes and diminished HDL anti-inflammatory function in patients several days after elective surgery.18


Figure 2. Schematic representation of enzymatic changes occurring within HDL as a result of the acute-phase response.



ApoA-1 and antioxidant enzymes are replaced by inflammatory proteins, rendering HDL less protective, and in some cases pro-inflammatory.

A-I = apolipoprotein A-I; A-II = apolipoprotein A-II; CETP = cholesteryl ester transfer protein; J = apolipoprotein J; LCAT = lecithin:cholesterol acyltransferase; PAF-AH = platelet activating factor acyl hydrolase; PLTP = phospholipid transfer protein; PON = paraoxonase; SAA = serum amyloid A; sPLA2 = secretory non-pancreatic phospholipase A2.

From: Rohrer L, Hersberger M, von Eckardstein A. Curr Opin Lipidol. 2004;15:269-278.
Used with permission.



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