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EDITORIAL COMMENT

High-Density Lipoproteins

From Function to Therapy*

Chunyu Zheng, SCD, Masanori Aikawa, MD, PHD

Boston, Massachusetts

The substantial residual cardiovascular events present instatin-treated patients provide a challenge to researchers inthe cardiovascular field to develop additional therapeuticapproaches. In cardiovascular disease (CVD) epidemiology,

few associations are as consistent and enduring as theinverse association between high-density lipoprotein cho-lesterol (HDL-C) levels and risk for coronary artery disease(1). Observational studies have shown that each 1-mg/dldecrease in HDL-C concentration is associated with a 2% to3% increased risk of CVD (2). This strong inverse relationshiphas stimulated interest in determining mechanisms and opti-mal management of low levels of HDL-C (3,4).

See page 2372

Clinical and pre-clinical evidence has established that

lowering of low-density lipoprotein cholesterol (LDL-C)levels reduces vascular inflammation and activation andprevents the onset of acute thrombotic complications of atherosclerosis (5,6). However, in contrast to observationalstudies that have consistently identified HDL-C as a potentcardioprotective factor, interventional CVD trials evaluatingHDL have so far been discouraging. Phase III trials withtorcetrapib and dalcetrapib, a class of drugs that elevate theconcentration of large, mature HDL through cholesterylester transfer protein (CETP) inhibition, were terminatedprematurely due to excess adverse events (7) and futility (8). Another study, AIM-HIGH (Atherothrombosis Interven-

tion in Metabolic Syndrome With Low HDL/High Trig-lycerides: Impact on Global Health Outcomes), which wasconducted to validate the benefit of raising HDL-C levelsthrough extended-release niacin in a group of high-risk patients with managed low LDL-C levels, failed to show any incremental clinical benefit, although the difference inHDL-C values between the niacin and placebo groups wasunexpectedly small, only 5.0 mg/dl (9). In addition, recent

Mendelian randomization studies in which functional ge-netic variants of apolipoprotein AI (apoAI), lecithin-cholesterol acyltransferase (LCAT), and endothelial lipaseapparently exhibited isolated effects on HDL-C level failedto show a causal relationship between genetically deter-

mined HDL-C level and predicted CVD risk, even whenHDL-C level and risk were strongly related in the back-ground population (10). Should we give up on HDL? Orshould we establish a new rationale behind HDL-raisingtherapy?

The dichotomy of findings from observational studiesand randomized trials emphasizes the complexity of HDLin vascular disease. It is becoming increasingly evident thatthe “quality” of HDL matters as much as its “quantity.” TheHDL-C blood levels do not necessarily capture the diverseatheroprotective functions of the heterogeneous HDL pop-ulations and may not be a reliable surrogate for causative

biological processes through which HDL protects againstatherosclerotic plaque development.

HDL may exert protective effects against CVD throughmultiple mechanisms. The most popular view is that HDLelicits cholesterol efflux from cholesterol ester–enrichedmacrophage foam cells in atheromata and transfers the excesscholesterol ester to the liver for excretion (11), a process termedreverse cholesterol transport (RCT) (Fig. 1). In addition toremoving excess plaque lipids, HDL exhibits anti-inflammatory, antithrombotic, and antioxidant effects andimproves endothelial function (4,11), which could alsocontribute to reduction in atherosclerosis. Accumulating

evidence suggests that HDL may lose its atheroprotectivefunctions in chronic and inflammatory diseases and becomedysfunctional (12). HDL may even gain atherogenic agents,as summarized in Figure 2. For example, the concentrationof HDL that contains apoCIII may directly (harmfully)associate with CVD (13). ApoCIII has proinflammatory,proatherogenic effects on cells that participate in atheroscle-rosis (14). HDL can acquire apoCIII during secretion by the liver or intestine or by transfer from very low-density lipoprotein while in the circulation (15).

Low HDL-C level represents a major lipid abnormality and CVD risk in patients with chronic renal disease (16).

This is particularly important because lowering LDL-Clevels with statins has diminished benefits in end-stage renaldisease (ESRD) (17). In this issue of the Journal , Yamamotoet al. (18) reported that HDL from patients with ESRDexhibited hallmarks of impaired atheroprotective functions:markedly reduced cholesterol efflux capacity, attenuatedantichemotactic ability, and increased proinflammatory ef-fects. HDL from patients undergoing statin therapy, al-though less proinflammatory, did not show improved cho-lesterol efflux function, suggesting independence amongdifferent atheroprotective functions of HDL (18). Thisinteresting clinical study is consistent with recent reports of

HDL proteome and lipidome. HDL from ESRD carries adistinct protein cargo, evidenced by enrichment of acute-

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital,Harvard Medical School, Boston, Massachusetts. Both authors have reported thatthey have no relationships relevant to the contents of this paper to disclose.

Journal of the American College of Cardiology Vol. 60, No. 23, 2012© 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.08.999



phase protein serum amyloid A1, lipoprotein-associatedphospholipase A2, and apoCIII (19).

Functionality studies like these are crucial for developingeffective HDL therapeutics to prevent/treat CVD. It isapparent that not all HDL particles are created equal, andno doubt the “method” of raising HDL levels has everythingto do with any clinical benefit conferred. HDL functionality

assessment, in addition to raising HDL particle concentra-tion (or HDL-C), would be a crucial part of any future drugdevelopment. Various functional aspects of HDL, includingthe following issues, deserve attention.

1. CETP inhibition remains a viable option to raiseHDL-C and lower LDL-C levels to reduce CVD risk.Studies to date have not supported an adverse effect of CETP inhibition on HDL function. The hypotheticalbenefit on atherosclerosis was offset by a molecule-specific off-target toxicity effect of torcetrapib (20), which was not shared by other CETP inhibitors, suchas anacetrapib and evacetrapib (21,22). On the other

hand, dalcetrapib, a partial CETP inhibitor, in con-trast to other CETP inhibitors, less effectively reduces

CETP activity and thus has a moderate effect onraising HDL-C levels and a negligible impact onlowering LDL-C levels. Therefore, outcome trials with anacetrapib and evacetrapib, with sound safety profiles and effective lipid modification, have thepotential to provide conclusive answers for the conceptof reducing the number of CVD events by CETP

inhibition (23). In the meantime, it is crucial to study the functionality of the raised HDL levels treated withCETP inhibitors.

2. ApoAI-based therapies. Infusion of reconstituted ordelipidated HDL dramatically raised plasma levels of pre-HDL, raised levels of lipid-poor cholesterol effluxacceptors and ligands for ATP-binding cassette trans-porter A1, and was shown to be able to cause a rapidreduction in atheroma burden (24). Additionally, infu-sion of lipid-poor HDL was also anti-inflammatory (25). Acute HDL therapy may be effective to prevent recur-rent events in high-risk patients. In addition to admin-

istration of HDL or apoAI mimetic peptides for short-term therapy, raising endogenous apoAI levels was

Figure 1 Overview of Reverse Cholesterol Transport and HDL Metabolism

High-density lipoprotein (HDL) is first secreted by the liver and small intestine as lipid-poor pre-HDL, which interacts with ATP-binding cassette transporter A1 (ABC-A1)

at peripheral tissues, such as macrophage foam cells in the atherosclerotic plaque, to initiate the reverse cholesterol transport process. Plasma-free cholesterol effluxed

from cells and incorporated into pre-HDL is esterified by the enzyme lecithin cholesterol acyltransferase (LCAT) with the formation of spherical HDL. Cholesterol ester

in plasma HDL derived from atherosclerotic plaque and other peripheral tissues is transported to the liver by either direct delivery through scavenger receptor BI

(SR-BI)–mediated selective cholesterol ester offloading or cholesteryl ester transfer protein (CETP)–mediated exchange of HDL cholesterol ester for apolipoprotein B

(apoB) lipoprotein-bound triglyceride (TG) and then low-density lipoprotein (LDL) receptor (LDL-R)–mediated uptake of the apoB lipoproteins. Current drug developmentfocuses on CETP inhibition, which blocks the exchange of cholesterol esters for triglyceride between HDL and apoB lipoproteins. CETP raises HDL-cholesterol (C) levels

primarily through expanding the population of mature, large HDL. Other potential interventions under clinical evaluation include administration of HDL or apoAI mimetic

peptide, inducers of endogenous apoAI synthesis, LCAT inducers, ATP-binding cassette transporter A1 activators, and selective liver X receptor agonists.

2381JACC Vol. 60, No. 23, 2012 Zheng and Aikawa

December 11, 2012:2380–3 High-Density Lipoproteins



shown to increase pre-HDL levels and enhance RCTand may be suitable for chronic use (26).

3. Identification of HDL components that directly affect itsatheroprotective functions. In addition to apoAI andapoAII, HDL carries more than 30 other proteins (19),and some of them are involved in lipid metabolism and vascular inflammation, including apoCIII, apoLI, andparaoxonase 1. These HDL modulators may be potentialtargets for drug development. They may also be used asbiomarkers to gauge HDL functionality.

4. RCT quantification and metrics of HDL “quality.” There is an urgent need for effective investigational and

clinical tools that measure HDL quality as well asquantity to guide drug development and evaluationthrough pre-clinical and early clinical phases beforeembarking on expensive large-scale CVD outcome trials.It was recently reported that the cholesterol efflux capac-ity of HDL, calculated from ex vivo cultured macro-phages, has a strong inverse association with regressionof coronary artery disease independent of plasmaHDL-C levels in a CVD imaging trial (27). Severallaboratories are also developing methods for quantifyingRCT in humans using stable isotopes. In addition toRCT, similarly principled metrics (28), with their anti-

inflammatory, antithrombotic, and antioxidant functionsmeasured, together with parameters of HDL quantity

(i.e., HDL particle number), will allow for global assess-ment of HDL’s atheroprotective functions.

In summary, low levels of HDL-C are associated withincreased cardiovascular risk, even among patients withaggressive statin regimens, which leads to the recommen-dation of raising HDL levels as a rational target. However,it is becoming increasingly apparent that not all HDLparticles are created equal and that the “quality” of HDLmatters as much as its “quantity.” Future research shouldexplore the most efficient methods of improving HDLquality, measuring functions of raised HDL levels by new therapies, as well as designing metrics of HDL multifaceted

atheroprotective functions.

Reprint requests and correspondence: Dr. Masanori Aikawa,Center for Excellence in Vascular Biology, Brigham and Women’sHospital, Harvard Medical School, 77 Avenue Louis Pasteur,NRB7, Boston, Massachusetts 02115. E-mail: [email protected].

REFERENCES

1. Boden WE. High-density lipoprotein cholesterol as an independent

risk factor in cardiovascular disease: assessing the data from Framing-ham to the Veterans Affairs High-Density Lipoprotein Intervention Trial. Am J Cardiol 2000;86:19L–22L.

Figure 2 Functional Versus Dysfunctional HDL

High-density lipoprotein (HDL) can become dysfunctional after exposure to an inflammatory environment and under certain chronic diseases. Colored circles in the illus-

tration represent markers of functional or dysfunctional HDL. The loss or modification of HDL-bound enzymes and proteins such as apolipoprotein AI (apoAI), apoE, para-

oxonase 1 (PON1), and acetylhydrolase (AH) reduces HDL cholesterol efflux capacity and attenuates its anti-inflammatory and antithrombotic functions. On the other

hand, addition of proinflammatory and prothrombotic proteins such as apoCIII, lipoprotein-associated phospholipase A2 (Lp-PLA2), and serum amyloid A1 (SAA1) also

contributes to formation of dysfunctional HDL. Lifestyle and pharmaceutical intervention may restore or even enhance HDL function, with or without affecting total HDL

cholesterol or HDL particle count in the blood.

2382 Zheng and Aikawa JACC Vol. 60, No. 23, 2012

High-Density Lipoproteins December 11, 2012:2380–3

mailto:[email protected]







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25. Dimayuga P, Zhu J, Oguchi S, et al. Reconstituted HDL containinghuman apolipoprotein A-1 reduces VCAM-1 expression and neoin-tima formation following periadventitial cuff-induced carotid injury inapoE null mice. Biochem Biophys Res Commun 1999;264:465–8.

26. Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small moleculethat increases apolipoprotein A-I and high-density lipoprotein cho-lesterol in vitro and in vivo. J Am Coll Cardiol 2010;55:2580–9.

27. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol effluxcapacity, high-density lipoprotein function, and atherosclerosis.N Engl J Med 2011;364:127–35.

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Key Words: atherosclerosis y HDL y kidney y macrophage y statin.

2383JACC Vol. 60, No. 23, 2012 Zheng and Aikawa

December 11, 2012:2380–3 High-Density Lipoproteins

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