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Editorial |
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
Address all correspondence and requests for reprints to: Sergio Fazio, Vanderbilt University School of Medicine, Division of Cardiology, 383 PRB 2220 Pierce Avenue, Nashville, Tennessee 37232-6300. E-mail: sergio.fazio{at}vanderbilt.edu.
Reverse cholesterol transport is the biological system in charge of avoiding accumulation of cholesterol in peripheral cells. This system is universally accepted as an important target for therapeutic maneuvers aimed at limiting the development of atherosclerosis, a disease characterized by accumulation of cholesterol-loaded macrophages in the subendothelial space of medium-caliber arteries (1). High-density lipoprotein (HDL) cholesterol (HDLC) concentration in plasma is commonly seen as an indicator of the efficiency of the reverse cholesterol transport, and because of the inverse relationship between HDLC levels and coronary disease rates in populations and clinical databases, interventions aimed at increasing HDLC are implemented in practice as part of a comprehensive cardiovascular prevention strategy (2). In other words, even though we accept the notion that HDL functions at an extravascular, extracellular level, we expect that increases in levels of circulating HDLC, irrespective of mechanism, will be able to confer protection against plaque formation.
HDL has a biphasic existence, with the first phase being dedicated to cholesterol acquisition and the second phase to cholesterol delivery. In the acquisition phase, the nascent HDL is rich in phospholipids and discoid in shape and uses its main structural component apolipoprotein AI (apoAI) to extract cholesterol from peripheral cells through a tightly regulated mechanism involving the transfer of excess intracellular free cholesterol via membrane transporters such as the ATP-binding cassette (ABC) types A1 and G1 (ABCA1 and ABCG1). The free cholesterol is promptly esterified by lecithin-cholesterol-acyltransferase and stored in the particle core. After the HDL has acquired enough cargo to assume the spherical configuration, its size expansion and compositional changes will eventually lead to a functional transition to the delivery stage, where the HDL aims at moving cholesterol to targets such as the liver cells, the adipocyte, or plasma lipoproteins such as very-low-density lipoprotein, remnants, and low-density lipoprotein (LDL) (the atherogenic apoB-containing lipoproteins) (3). The transfer between HDL and liver cell is mediated by the scavenger receptor type B1 (SR-B1), a noninternalizing member of the scavenger receptor family, which allows for the HDL cholesterol cargo to move inside the cell while freeing the remaining cholesterol-poor HDL particle for another round of peripheral cholesterol collection (4). The hepatic delivery of HDLC is seen as beneficial because it drives cholesterol centripetally, toward the biliary compartment and possibly the fecal route. Transfer of lipids between HDL and apoB-containing lipoproteins is instead mediated by the cholesteryl ester transfer protein (CETP), whose effect is to deflate the HDL while enriching the atherogenic lipoproteins with cholesterol (5). This interparticle transfer is seen as deleterious because it reroutes cholesterol into a centrifugal pattern and possibly contributes to plaque formation. Therefore, inhibition of CETP has been considered for many years a target of therapy to raise HDLC and reduce atherosclerosis. However, the possibility exists for CETP to be inherently a good player in reverse cholesterol transport, expediting the movement of cholesterol and enhancing the functionality of the HDL particle. Such concerns are reduced by the recent discovery that cellular cholesterol efflux is not limited to acceptors such as the nascent HDL, and a prominent pathway based on ABCG1 is apparently devoted to exchange cellular cholesterol with larger HDL particles (6). In agreement with this, it has recently been reported that the large HDL that accumulate in plasma from CETP-deficient subjects are excellent drivers of cholesterol efflux from cholesterol-loaded macrophages via ABCG1-mediated mechanisms, an effect that in vivo could be responsible for more efficient cholesterol exit from the plaque (7). CETP is also capable of facilitating cholesterol transfer between HDL and particular cell types. To this end, it is particularly interesting that the acquisition of cholesterol by the adipocyte is controlled by two alternative mechanisms, one mediated by SR-B1, as in hepatocytes, and the other mediated by CETP, as in inter-lipoprotein transfer (8). Currently, CETP inhibitors are being clinically tested to determine whether the substantial increases in HDLC levels they cause are accompanied by beneficial changes at the level of the plaque or in terms of cardiovascular disease (CVD) rates in high-risk patients (9).
The uncertainties on the therapeutic possibilities of HDL manipulations based on CETP inhibition come from experimental, clinical, and epidemiological data. Experimentally, although most of the work conducted in the mouse (an animal model spontaneously deficient in CETP) supports the notion that transgenic expression of CETP will reduce HDLC levels and cause accelerated atherosclerosis (10, 11), there have been data pointing at the exact opposite direction, particularly with obese and diabetic mice (12). Clinically, it is known that the large HDL increases resulting from complete CETP deficiency have not been clearly linked to vascular protection and at times have been associated with increased cardiovascular risk (13, 14). Moreover, obese subjects who develop diabetes have reduced CETP activity (15). Epidemiological studies have exploited the many common polymorphisms of the CETP gene that are associated with CETP mass and function in plasma and with HDLC levels. Most studies have suggested that CETP polymorphisms associated with higher HDL are also linked to cardiovascular protection, but there are studies showing lack of any correlation and some supporting the notion for a direct effect of CETP levels or function on cardiovascular risk independent from HDL (16). Indeed, the hypothesis has been suggested that HDL increases resulting from specific genetic polymorphisms of CETP may be less beneficial than equivalent HDL increases from other causes. Dozens of polymorphisms have been reported, with the most commonly studied being the promoter polymorphism at –629C
A (influencing gene expression and CETP levels), the intron 1 polymorphism at position 277 defined as TaqI B1/B2 (in strong linkage disequilibrium with the –629CA polymorphism), and the isoleucine to valine change at position 405 (affecting structure and function of CETP) (16).
The paper of Borggreve et al. (17), in this issue of the Journal, reports on the association between polymorphisms in the CETP locus and incidence of cardiovascular events, mostly hospitalizations and deaths for myocardial infarction and ischemic heart disease, in a large free-living population with low CVD risk, low prevalence of dyslipidemia and diabetes, but higher prevalence of albuminuria (the PREVEND study). The three polymorphisms studied were the ones discussed above, but most of the data center on the promoter polymorphism at –629. The study confirmed previous work showing that the homozygous and heterozygous carriers of the –629A and the TaqI B2 polymorphisms have higher HDL levels than the carriers of the –629C and TaqI B1 polymorphisms. This was likely because of a significantly decreased CETP mass and activity in the plasma of carriers of the –629AA or the TaqI B1B1 genotypes (ranging between –27 and –23%). Paradoxically, in both cases, the presence of the polymorphism producing lower CETP levels, reduced CETP function, and increased HDL levels was also associated with significantly higher incidence of hard cardiovascular outcomes in the 5-yr period of the study. It must be emphasized that CVD rates in this population were not determined retrospectively or cross-sectionally but collected prospectively according to a predefined, rigorous protocol.
Before getting too alarmed by the realization that plasma HDL may suddenly change camp in risk predictivity, one should be comforted by the data that the baseline HDLC levels were, as expected, inversely related to cardiovascular risk. Moreover, after correction for HDLC, the correlation between the CETP polymorphism and increased cardiovascular event rate was maintained, suggesting an independent effect of lower CETP levels on atherosclerosis. This means that the increased HDLC levels of the –629AA and TaqI B1B1 subjects were not involved in predicting the worst CVD outcomes. Only a small mention of the 405V polymorphism was made, because it did not show an effect on CVD independent from its effect on HDL.
How could reduced CETP activity possibly be associated with increased cardiovascular risk when it raises HDLC levels? The reasons may be unrelated to plasma HDL concentrations. For example, a reduced entry of HDLC in the adipocyte, partly controlled by CETP, may limit the ability of the cell to appropriately expand in size at times of triglyceride accumulation. The adipocyte is unable to synthesize enough cholesterol to keep pace with the demands of intense membrane synthesis, and it is plausible to speculate that limiting membrane expansion may stress the adipocyte into a proinflammatory state, determining macrophage recruitment into the adipose tissue and inducing or aggravating insulin resistance (18). Indeed, the function of CETP appears to be important in other cellular functions, because CETP polymorphisms have been found to associate with the deposition of ß-amyloid plaque in subjects with the apoE4 allele (19). However, it is also possible that the supposed direct effects of CETP on vascular disease may be caused by other genes in close proximity to CETP on the long arm of chromosome 16 (16q21) and whose expression may be in linkage disequilibrium with common CETP haplotypes. A search of the chromosomal surrounding of the human CETP gene reveals the presence, for example, of the amyloid ß-precursor protein-binding protein 1 (http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l118470).
The study of Borggreve et al. (17) proposes the strongest evidence to date for a discrepancy between the beneficial effects of reduced CETP activity on cardiovascular disease mediated by the increase in plasma HDL and its possible negative effects mediated by mechanisms not related to HDLC concentration.
The results of this interesting study could hamper the excitement around the development and clinical testing of CETP inhibitors as agents to increase HDL and reduce atherosclerosis. However, pharmacological CETP inhibition may have advantages over genetically controlled variations in CETP protein levels. First, small molecules such as torcetrapib inhibit only circulating CETP, in this way producing the beneficial plasma HDL increase without the possible negative effects mediated by inhibiting intracellular CETP (20). Second, CETP inhibitors will be targeted to patients with enhanced cardiovascular risk resulting from low HDL syndromes, which are not well represented in epidemiological studies such as the one in this issue of the Journal. Indeed, the mean HDLC levels in the PREVEND study were well above the accepted guideline threshold level of 40 mg/dl, and the HDL difference between homozygous genotypes of the –629 polymorphism was about 10%, or approximately 5 mg/dl. It is likely that in subjects with low HDL, the protective effects of larger HDLC increases (expected at around 50% for a common dose of CETP inhibitor) will overwhelm and overrule any possible direct negative effects of reduced CETP activity. Finally, CETP inhibitors have shown an ability to reduce LDL cholesterol concentrations and will be used together with LDL-lowering agents, adding to an effect that is universally accepted as most beneficial to the vasculature.
The lesson from the PREVEND study is that we need to continue to apply extreme care in approaching the reverse cholesterol transport pathway as a target for therapeutic interventions and that the notorious inverse correlation between HDLC levels and CVD rates should not reassure us that higher is always better.
Footnotes
This work was supported by National Institutes of Health Grant HL65709.
Abbreviations: ABC, ATP-binding cassette; apoAI, apolipoprotein AI; CETP, cholesteryl ester transfer protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDLC, HDL cholesterol; LDL, low-density lipoprotein; SR-B1, scavenger receptor type B1.
Received June 14, 2006.
Accepted June 21, 2006.
References
4 allele. J Neurol 253:181–185[CrossRef][Medline]This article has been cited by other articles:
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  I. Porchay-Balderelli, F. Pean, N. Bellili, R. Jaziri, M. Marre, F. Fumeron, and for the DIABHYCAR Study Group The CETP TaqIB Polymorphism Is Associated With the Risk of Sudden Death in Type 2 Diabetic Patients Diabetes Care, November 1, 2007; 30(11): 2863 - 2867. [Abstract] [Full Text] [PDF]
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