COMMENTARIES

Impaired HDL-mediated Cholesterol Efflux in Metabolic Syndrome Subjects

Paul Nestel and Dmitri Sviridov, Baker IDI, Heart & Diabetes Institute, Melbourne, Australia

In a recent study of 25 men with metabolic syndrome, we found that when their plasmas were incubated with macrophages pre-labeled with radiocholesterol there was not the anticipated positive correlation between HDL cholesterol (HDL-C) and cholesterol efflux from the cells [1]. On the contrary the correlation was negative and similar to that between efflux and LDL-C concentration. Thus HDL, like LDL, appeared to donate more cholesterol to the THP-1 macrophages (activated with LXR agonist) than was accepted through efflux. When apoB lipoproteins were removed the paradoxical relationship between influx and HDL-C remained although the absolute efflux was reduced by the contribution from apoB lipoproteins that can also serve as acceptors of cellular cholesterol at least in vitro.

            We ascribe this effect to reflect dysfunctionality of HDL particles. A possible effect of HDL particle numbers was eliminated by correcting data to apoA-I concentration. One characteristic of these HDL was their relative enrichment with apoA-II suggesting that these were smaller triglyceride-rich particles. Dysfunctional HDL have been described in several cardiovascular and metabolic disorders and evaluated by reduced capacity to oppose inflammatory effects or to prevent oxidation of LDL [2]. In fact HDL from subjects with coronary artery disease may be pro-oxidant as well as pro-inflammatory [3]. Several assays of inflammation have been reported, the most frequent being that of failure to correct impaired endothelial dysfunctionality measured as the increased expression of endothelial adhesion molecules. Dysfunctional HDL may promote rather than inhibit the expression of MCP-1 [4], through which monocyte recruitment into the arterial wall occurs.

            Our studies as indeed most studies of cholesterol efflux have been carried out in vitro. Under such conditions the measurement includes other parameters of reverse cholesterol transport (RCT) including LCAT and CETP activities that respectively esterify effluxed cholesterol and redistribute the cholesteryl esters among lipoproteins. Plasmas from subjects with metabolic syndrome show increased CETP activity whereas it has been shown that HDL from CETP-deficient plasmas promote efflux in vitro [5]. This effect is partly related to increased LCAT-mediated cholesterol esterification in the medium. Cholesterol flux, measured in vitro, is bidirectional but as we and others [6] have shown, under normal circumstances, cholesterol flux is predominantly that of efflux.

            Interestingly, when the subjects in our study were treated with a statin, rosuvastation, the inverse relationship between plasma HDL-C concentration and cholesterol efflux diminished and was no longer statistically significant. Statins in general lower CETP mass and activity, as we found also in this study. This probably contributed to the shift from smaller apoA-I/apoA-II particles to larger apoA-I particles as well as to an increase in efflux (although the net effect was still one of apparently relatively greater influx).

            Simvastatin treatment reverses also the pro-inflammatory effect of abnormal HDL [3]. Cholesterol efflux leads to the initial formation of preβ-HDL particles that in turn further stimulate efflux; however we did not observe an increase in such nascent HDL particles after statin treatment.

            The structural changes in HDL that may diminish its capacity to stimulate cholesterol efflux are not clear. However the metabolic derangements that may occur in patients with metabolic syndrome include modification of apoA-I by advanced glycation end products (AGE) or through oxidation by myeloperoxidase that results in both instances in diminished ABCA1-mediated cholesterol efflux [7,8]. Such effects can lead to the formation of a pro-inflammatory population of HDL with the loss of its atheroprotective characteristics [2,3].

            Whereas efflux of cholesterol from cells either to apoA-I via the ABCA1 transporter, or to HDL via the ABCG1 transporter, is the means for the removal of cholesterol from extrahepatic cells, it is not clear whether impaired RCT increases the risk of atherosclerosis. Such a possibility had been suggested by Mikkola et al. [9] who observed in postmenopausal cynomolgus monkeys an inverse correlation between cholesterol efflux (when sera from the monkeys were incubated with Fu5AH cells) and the severity of coronary artery atherosclerosis. However uncertainty about the clinical importance of cholesterol efflux has been recently emphasized by the demonstration that subjects with the genetic deficiency of ABCA1 who show both reduced HDL-C concentrations and diminished cholesterol efflux from macrophages (measured in vitro) do not appear to suffer from excess coronary heart disease [10]. In the latter study, HeLa cells were transfected with three ABCA1 mutants that occurred among the patients and efflux to increasing concentrations of apoA-I was measured. Another possible paradox is that the formation of preβ-HDL particles through cholesterol efflux may not represent a protective mechanism since Asztalos and colleagues [11] have shown a positive relationship between the concentration of plasma preβ-HDL and coronary heart disease.

            Since we had previously reported that in healthy athletes plasma HDL concentration correlated positively with cholesterol efflux measured in vitro [12], we conclude that the negative or inverse correlation between these parameters reflects impairment of one more HDL functions in subjects with metabolic syndrome. The concept of dysfunctional HDL which postulates that the multifunctional properties of HDL may in time be shown to predict future cardiovascular events more strongly than the HDL concentration itself has been reviewed a number of times [including 2,4,13]. Studies with apoA-I peptides have already demonstrated that different antiatherogenic functions such as antioxidant capacity and promotion of cholesterol efflux may be mediated by different peptides within the whole molecule [14]. It therefore may not be the case that impairment of capacity to stimulate cholesterol efflux such as our study has shown would also impair other antiatherogenic functions of HDL. It is of interest, however, that treatment with a statin partly reversed this dysfunction.

References

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