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Re‐examining the high‐density lipoprotein hypothesis

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Title Re-examining the high-density lipoprotein hypothesisAuthor(s) Tan, KCBCitation Journal of Diabetes Investigation, 2016, v. 7 n. 4, p. 445-447Issued Date 2016URL http://hdl.handle.net/10722/229317Rights This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Re-examining the high-density lipoproteinhypothesisA low level of high-density lipoprotein cholesterol (HDL-C) isan important cardiovascular risk factor, and is commonly seenin patients with type 2 diabetes mellitus. An inverse relation-ship between HDL-C concentration and cardiovascular risk hasbeen consistently shown in clinical and epidemiological studies.In the well-known Framingham Heart Study, HDL-C wasfound to be the best predictor of cardiovascular mortality. Therecent Emerging Risk Factors Collaboration Study has alsoshown that the strong inverse association between the risk ofcoronary artery disease and HDL-C levels remained even afteradjusting for other lipid and non-lipid risk factors. As a keyindependent cardiovascular risk factor, measurement of HDL-Chas been incorporated into the majority of the risk stratiﬁcationmodels for prediction of cardiovascular risk. It has been esti-mated that cardiovascular risk decreases by approximately 2–3% per 1-mg/dL increase in HDL-C. In light of the strongexperimental and epidemiological data supporting a protectiverole for HDL in atherosclerosis, substantial research efforts havebeen directed at developing strategies to harness the ‘atheropro-tective’ function of HDL, and raising HDL-C has become apotential therapeutic target over the past decade.However, the ‘HDL hypothesis’ suggesting that HDL plays acausal role in the pathogenesis of atherosclerotic cardiovasculardisease has recently been challenged by large-scale humangenetic studies. The ﬁrst genetic study to cast doubt on the cau-sal role of HDL used a Mendelian randomization approach todetermine whether single-nucleotide polymorphisms (SNPs)associated with increased levels of HDL-C were also linked tochanges in the risk of coronary heart disease. Voight et al.1reported that SNPs associated with high levels of low-densitylipoprotein cholesterol increased the risk of myocardial infarc-tion, but surprisingly, no relationship could be found betweenSNPs that raised HDL-C and coronary heart disease risk. Fur-thermore, subsequent genome-wide association studies alsofailed to show correlations between the magnitude of the effectsize of additional HDL-associated SNPs identiﬁed and the mag-nitude of the effect size on coronary heart disease. These analy-ses have therefore created skepticism about the causal role ofHDL in atherosclerotic cardiovascular disease.Another severe blow to the HDL hypothesis comes from thedisappointing results of a number of clinical trials on agentsraising HDL-C. So far, pharmacological interventions thatincrease HDL-C concentration have not shown improvementin cardiovascular outcomes when added to standard statin ther-apy2. Two large trials with the currently available major HDL-C raising agent, niacin – the Atherothrombosis Intervention inMetabolic syndrome with low HDL/high triglycerides: impacton Global Health outcomes (AIM-HIGH) trial and the HeartProtection Study 2 – Treatment of HDL to Reduce the Inci-dence of Vascular Events (HPS2-THRIVE) – failed to show sig-niﬁcant cardiovascular beneﬁt. This would suggest that raisingHDL-C levels, at least with niacin, did not confer any addi-tional clinical beneﬁt on top of that achieved by statin therapy.Inhibitors of cholesteryl ester transfer protein (CETP), whichare being developed speciﬁcally as HDL-C raising drugs,increase HDL-C to a much greater extent than niacin. Short-term clinical trials have demonstrated up to 60–70% increase inHDL-C with some of the more potent CETP inhibitors. How-ever, torcetrapib, the ﬁrst CETP inhibitor to enter clinical devel-opment, not only failed to reduce cardiovascular risk butactually increased cardiovascular and total mortality due to itsoff-target effects. The Dal-OUTCOMES study, a phase 3 pla-cebo-controlled randomized controlled trial of dalcetrapib inpatients with a recent acute coronary syndrome, was stoppedearly after no signiﬁcant improvement in overall or cardiovas-cular related mortality and related events was found. It has justbeen announced that the development of another CETP inhibi-tor, evacetrapib, would be discontinued after independent datamonitoring committee advised a halt to the phase 3 random-ized trial in patients with high risk coronary artery disease[Assessment of clinical effects of cholesteryl ester transfer pro-tein inhibition with evacetrapib in patients at a high-risk forvascular outcomes (ACCELERATE)] due to insufﬁcient efﬁcacy.This leaves the Randomized Evaluation of the Effects of Anace-trapib through Lipid-modiﬁcation (REVEAL) trial as the onlyongoing phase 3 cardiovascular outcome trial of CETP inhibitorin patients with established vascular disease. The trial isexpected to be completed in 2017 and the results will be criticalin determining whether CETP inhibitor has a place in clinicalcare.So is the ‘HDL hypothesis’ truly defunct? It should bepointed out that the HDL hypothesis has always been relatedto HDL function rather than to HDL-C content. Simply raisinglevels of HDL-C level cannot be directly inferred to as improv-ing HDL function. Likewise, in human genetic studies, theextent to which the SNPs that are associated with increases inHDL-C are also linked to relevant changes in HDL function isuncertain. It is clear that the complex nature of HDL metabo-lism and function cannot be determined by just quantifyingHDL-C alone. HDL particles are highly heterogeneous andª 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 7 No. 4 July 2016 445This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distributionin any medium, provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adaptations are made.EDITORIALconsist of multiple forms and components, and this heterogene-ity in HDL structure is intrinsically related to their functionaldiversity. Measurement of HDL-C content does not necessarilyreﬂect the distribution or overall abundance of HDL subspecies.Structure-function analyses have shown that HDL-C is a ratherpoor indicator of the functionality of HDL. Experimental datahave suggested that HDL has multiple protective functionsagainst atherosclerosis. One of the best characterized functionsof HDL is its role in reverse cholesterol transport. By acting asextracellular cholesterol acceptors in the circulation, HDL canpromote cholesterol efﬂux from cells like macrophages in theartery wall (Figure 1). In addition, HDL has anti-oxidative,anti-inﬂammatory and anti-apoptotic properties. HDL has beenreported to block oxidative modiﬁcation of LDL and decreaseadhesion molecules expression. It also promotes endothelialrepair and ameliorates endothelial dysfunction. Which subclass(es) of HDL species are responsible for which aspects of biolog-ical activities of HDL is poorly understood. To make matterseven more complicated, changes in the proteome and/or lipi-dome of HDL particle may adversely affect the functionality ofHDL. A number of pathological conditions including diabetesmellitus can trigger structural and functional alterations inHDL and many proteins other than apolipoproteins may bindto HDL. One such example is serum amyloid A, and bindingof serum amyloid A impairs the ability of HDL to efﬂuxcholesterol from cells3. As a result, HDL can lose its atheropro-tective properties, and become dysfunctional and pro-inﬂamma-tory under certain circumstances. The degree of loss of normalHDL function and gain of dysfunction might differ with respectto the different biological activities of HDL. How changes inthe proteome and/or lipidome of HDL affect the functionalityof HDL is currently under intense investigations.Clinical measures to determine the different aspects of HDLfunction are being developed and evaluated in a number ofresearch laboratories. The most widely-studied and well-charac-terized HDL function is probably its cholesterol efﬂux capacity.Ex vivo assays have been used to assess the capacity of individ-ual patient HDL specimens or serum to remove cholesterolfrom cultured cholesterol-loaded macrophages. The relationshipbetween HDL cholesterol efﬂux capacity and cardiovascular dis-ease has been examined in cross-sectional and longitudinalstudies. It has been shown that HDL-C levels only explain afraction (approximately one-third) of the variance in the choles-terol efﬂux capacity of HDL. An independent inverse associa-tion between HDL cholesterol efﬂux capacity and incidentcardiovascular events has been shown both in the Dallas HeartStudy and in the European Prospective Investigation of Cancer-Norfolk study4,5. Measurement of this classic function of HDLhas an even stronger relationship with coronary heart diseasethan measures of HDL-C, and the relevance of HDL function-Macrophage foam cellABCA1ABCG1FC FCLCATLipid-poor apoA-I Discoidal HDL Small spherical HDL Larger spherical HDLLCATFCFCFC FCSRB1Figure 1 | Cellular cholesterol efflux to high-density lipoprotein (HDL). Efflux of free cholesterol (FC) from cells to extracellular HDL-based acceptorsis mediated by the action of active transporters and passive diffusion. This first step of reverse cholesterol transport is influenced by thephysicochemical properties of HDL and the interaction of these HDL subclasses with cellular transporters. The adenosine triphosphate-bindingcassette transporter A1 (ABCA1) interacts with cholesterol-deficient and phospholipid-depleted apolipoprotein A-I complexes, whereas ABCG1 andscavenger receptor B1 (SRB1) interact with spherical HDL particles of various sizes. After efflux to HDL, FC is esterified in the plasma by lecithin-cholesterol acyltransferase (LCAT), and is ultimately transported from HDL to the liver, either directly through SRBI or after transfer toapolipoprotein B-containing lipoproteins by the cholesteryl ester transfer protein for ultimate disposal in the feces.446 J Diabetes Investig Vol. 7 No. 4 July 2016 ª 2016 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, LtdE D I T O R I A LTan http://onlinelibrary.wiley.com/journal/jdiality to cardiovascular disease has ﬁnally been conﬁrmed inthese clinical studies. Taken together, available data show thatHDL cholesterol efﬂux capacity is predictive of prevalent andincident coronary heart disease independent of HDL-C, andevaluation of HDL function rather than HDL mass such asHDL-C might be much more informative.In conclusion, HDL-C is not a good surrogate marker ofHDL function. Measurement(s) of HDL function rather thanHDL-C might be a better tool to evaluate the therapeuticresponse of interventions targeting HDL, and could also fur-ther improve the assessment of cardiovascular risk. However,standardized assays of HDL function are not yet available forroutine clinical use, and a number of issues need to beaddressed. As HDL has multiple functions, there is currentlyno consensus on which function(s) of HDL are key to itsantiatherogenic effect, and what the optimal test(s) to charac-terize HDL function are. Because of the heterogeneity of HDL,measurement of HDL particles and distribution of subspeciesneeds to be validated in order to standardize assays of func-tionality with HDL quantiﬁcation. The assays of HDL functionalso need to be reproducible and cost-effective. HDL is one ofthe most biologically variable molecules, and the ‘HDL func-tion hypothesis’ still holds potential as a means to reduce car-diovascular disease.DISCLOSUREThe author declares no conﬂict of interest.Kathryn Tan*Department of Medicine, Queen Mary Hospital,University of Hong Kong, Hong Kong*E-mail: kcbtan@hkucc.hku.hkREFERENCES1. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDLcholesterol and risk of myocardial infarction: a mendelianrandomisation study. Lancet 2012; 380: 572–580.2. Keene D, Price C, Shun-Shin MJ, et al. Effect oncardiovascular risk of high density lipoprotein targeted drugtreatments niacin, fibrates, and CETP inhibitors: meta-analysisof randomised controlled trials including 117,411 patients.BMJ 2014; 349: g4379.3. Tsun JG, Shiu SW, Wong Y, et al. Impact of serum amyloid Aon cellular cholesterol efflux to serum in type 2 diabetesmellitus. Atherosclerosis 2013; 231: 405–410.4. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol effluxcapacity and incident cardiovascular events. N Engl J Med2014; 371: 2383–2393.5. Saleheen D, Scott R, Javad S, et al. Association of HDLcholesterol efflux capacity with incident CHD events: aprospective case control study. Lancet Diabetes Endocrinol2015; 3: 507–513.Doi: 10.1111/jdi.12487ª 2016 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 7 No. 4 July 2016 447E D I T O R I A Lhttp://onlinelibrary.wiley.com/journal/jdi Editorial

Re-examining the high-density lipoprotein hypothesis

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