Mediterranean Approach to Improving High-Density Lipoprotein Function
2017; Lippincott Williams & Wilkins; Volume: 135; Issue: 7 Linguagem: Inglês
10.1161/circulationaha.117.026278
ISSN1524-4539
Autores Tópico(s)Fatty Acid Research and Health
ResumoHomeCirculationVol. 135, No. 7Mediterranean Approach to Improving High-Density Lipoprotein Function Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMediterranean Approach to Improving High-Density Lipoprotein Function Daniel J. Rader, MD Daniel J. RaderDaniel J. Rader From Departments of Genetics, Medicine, and Pediatrics and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Originally published14 Feb 2017https://doi.org/10.1161/CIRCULATIONAHA.117.026278Circulation. 2017;135:644–647Article, see p 633The complex interrelationships among diet, high-density lipoprotein (HDL), and cardiovascular risk have been a topic of great interest for decades.1 HDL cholesterol (HDL-C) levels are strongly inversely associated with cardiovascular disease (CVD). Diets high in saturated fat are strongly positively associated with CVD. Yet, diets high in saturated fat increase HDL-C levels, and low-fat diets reduce HDL-C levels,1 a paradox that has never been fully reconciled. However, the past several years have provided insights into the relationship between HDL-C and CVD that may help to reconcile these disparate findings. Specifically, the "HDL hypothesis" that HDL-C is causally related to CVD and that intervention to increase HDL-C will reduce CVD risk has been largely disproven.2 Genetic studies in humans have shown that certain genetic variants that increase HDL-C are not associated with protection from CVD.3,4 Furthermore, pharmacological interventions that raise HDL-C levels such as niacin and cholesteryl ester transfer protein (CETP) inhibitors have failed to reduce CVD events in large randomized clinical trials.2,5 In this context, the fact that low-fat diets reduce HDL-C levels but do not increase risk of CVD can be reasonably interpreted: The reduction of HDL-C does not causally increase the risk of CVD.However, studies in the last several years have given rise to an alternative hypothesis, namely the "HDL flux" or "HDL function" hypothesis.5 This concept is based on the idea that HDL has a number of putative antiatherogenic functions that may causally affect CVD risk but that are not directly related to simple measures of HDL mass such as HDL-C levels. The best established of the measures of HDL function is HDL cholesterol efflux capacity (CEC), an ex vivo measure of the ability of an individual's HDL to promote cholesterol efflux from macrophages in cell culture.6 A number of studies have shown that HDL CEC is inversely associated with prevalent coronary artery disease7 and incident CVD events8,9 even independently of HDL-C levels. Although this is consistent with the concept of a protective effect, it is still only an association that is far from proof of causality. A number of other HDL functionality measures have been described,10 although none have been studied in the large numbers of individuals that CEC has, and therefore, their relationship to CVD, especially incident CVD events, remains uncertain.Interventions that increase CEC are one approach to establishing a body of data that CEC could causally protect against atherosclerosis, and there are several positive examples in preclinical models.5 However, to date, there are relatively few rigorous studies of the effects of interventions on HDL CEC or other measures of HDL functionality.6 Statins modestly reduce HDL CEC.11 Niacin does not increase CEC despite its effect in increasing HDL-C levels.12 It is interesting to note that CETP inhibitors appear to increase HDL CEC, although their effects, especially on the ABCA1-specific CEC, are substantially blunted by high-intensity statin therapy.11 Infusions of recombinant apolipoprotein A-I containing HDL markedly increase CEC13 and are in clinical development. Given the known relationships of diet to both HDL-C levels and CVD risk, the impact of different dietary interventions on CEC is of particular interest. In this issue of Circulation, Hernáez et al report the largest, longest, and most rigorous study of the impact of a dietary intervention on HDL CEC and other measures of HDL functionality.14 They analyzed samples from a subset (n=296) of the PREDIMED study (Prevención con Dieta Mediterránea; n=7447) comparing the effects of a traditional Mediterranean diet (TMD) with a low-fat diet. This landmark study demonstrated that a TMD in individuals without preexisting CVD significantly reduced cardiovascular events compared with a low-fat diet.15 In the present HDL functionality study, the investigators analyzed stored samples before and after 1 year of randomization to diet. Within the TMD group, 1 subgroup (n=100) was supplemented with virgin olive oil (VOO) and the other with nuts (n=100). All groups were compared after 1 year on the diet with their baseline values, and the 3 dietary interventions were also compared with each other. The results advance our understanding of the effects of dietary intervention on measures of HDL functionality.It is interesting to first review the results for the low-fat diet group, particularly because the effects of a low-fat diet on HDL function have never been formally studied. Despite evidence that the subjects adhered to the low-fat diet (especially reduced saturated fat intake), confirmed by the expected significant reduction in LDL-C levels, there was only a nonsignificant trend toward reduction in the HDL-C levels, possibly related to power (n=96 in the low-fat diet group). In contrast, there was a trend toward an increase in HDL CEC in the low-fat diet group. It is possible that in a larger subset, this differential between reduction in HDL-C and increase in HDL CEC could have been statistically significant. Although not definitive, this suggestive finding may shed some light on the differences of a low-fat diet on HDL mass versus HDL function and itself merits further investigation.The contrasts between the TMD groups and the low-fat diet group are instructive. Both TMD groups also had a trend toward reduction in HDL-C that, if anything, was greater than for the low-fat diet group. In contrast to the trend toward reduced HDL-C, both TMD groups had a statistically significant increase in HDL CEC. It is notable that both TMD groups had similar effects, indicating that it was the TMD, not the olive oil or nuts, that had this effect on HDL CEC. Effects on other measures of HDL function were generally insignificant or inconsistent between the 2 groups, although it is interesting to note that both TMD groups (but not the low-fat diet group) had a trend toward increased ability of HDL to promote nitric oxide production (HDL vasodilatory capacity) even though only the TMD-VOO group was statistically significant (If both groups had been analyzed together, this result would clearly have been significant). Thus, the TMD increases the classic HDL functionality parameter even as it decreases the classic HDL mass measurement. Whether this effect of the TMD contributes to its cardiovascular benefits remains uncertain.What are the mechanisms by which the TMD increases HDL CEC? Some clues may arise from other measurements made of the HDL. Although there were no significant changes in the plasma levels of apolipoprotein A-I, there was a significant decrease in the ratio of HDL-C to apolipoprotein A-I in both TMD groups (but not in the low-fat diet group). This suggests a reduction in core cholesteryl ester relative to surface apolipoprotein A-I, which could indicate an increase in hepatic activity of the scavenger receptor class B-I. Hepatic scavenger receptor class B-I reduces HDL-C levels but promotes HDL CEC and overall reverse cholesterol transport,5 and genetic reduction in scavenger receptor class B-I activity increases HDL-C levels but paradoxically increases cardiovascular risk.4 It is intriguing to speculate that the TMD may result in upregulation of hepatic scavenger receptor class B-I, which would be consistent with many of the findings. It is also interesting to note that HDL had a greater ability to esterify cholesterol, a function of the enzyme lecithin-cholesterol acyltransferase, after the TMD-VOO diet (but not the TMD-nuts diet). Increased lecithin-cholesterol acyltransferase activity has been suggested to promote reverse cholesterol transport and to potentially be antiatherogenic.16 Both TMD groups had a modest but significant reduction in the HDL triglyceride content. This could be consistent with reduced CETP-mediated transfer of triglycerides into HDL (Indeed, the TMD-VOO group, but not the TMD-nuts group, had reduced CETP activity). HDL phospholipid content was increased in the TMD-VOO diet group (but not the TMD-nuts group) compared with the low-fat diet group. HDL phospholipid is an important determinant of HDL CEC.17,18 This finding suggests that the TMD-VOO diet may have reduced the activity of endothelial lipase, an enzyme that hydrolyzes HDL phospholipid and is a major regulator of HDL metabolism and potentially function.There are many differences between the TMD and the low-fat diet that may account for the differences observed here. One possible difference is alcohol intake. The TMD participants were instructed that "when the volunteer consumed alcohol, to moderately drink red wine (1 small glass/meal)," whereas the low-fat diet participants were given no similar instructions. Alcohol consumption is known to influence HDL-C levels and has been shown in a small experimental study to promote CEC.19 It would be of interest to know whether alcohol use actually differed between the TMD and low-fat diet groups, although this is unlikely to explain the reported differences in this study.It is interesting to note that adherence to a Mediterranean diet was recently shown to be associated with slower progression of age-related macular degeneration (AMD).20 Considerable genetic evidence suggests that HDL metabolism is related to AMD, with genetic variants in CETP and hepatic lipase (LIPC) having strong associations with AMD.21 In addition, the retinal pigment epithelium has been shown to express many HDL-related genes and has the capacity to efflux cholesterol to HDL acceptors.22 Thus, it is possible that the TMD, by enhancing HDL function, could slow the progression of AMD in addition to atherosclerosis.In summary, the interrelationships among diet, HDL, and CVD are highly complex. In the largest and longest study to date of the effects of a randomized dietary intervention on HDL function, Hernáez et al demonstrate a dissociation between the effects of a TMD on HDL-C levels (trending lower) versus on HDL CEC (significantly higher) and greater positive effects of the TMD on CEC compared with those of a low-fat diet. Although efforts to promote HDL CEC through pharmacological means are still in clinical development, these results indicate that a Mediterranean diet is a practical lifestyle-focused approach to improving HDL function and has the proven benefit of reducing cardiovascular risk and the potential to reduce the progression of AMD. Whether promotion of HDL CEC causally contributes to the benefits of the Mediterranean diet remains to be established.DisclosuresDr Rader is a founder of VascularStrategies.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Daniel J. Rader, MD, Perelman School of Medicine, University of Pennsylvania, 11-125 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104. E-mail [email protected]References1. Baum SJ, Kris-Etherton PM, Willett WC, Lichtenstein AH, Rudel LL, Maki KC, Whelan J, Ramsden CE, Block RC.Fatty acids in cardiovascular health and disease: a comprehensive update.J Clin Lipidol. 2012; 6:216–234. doi: 10.1016/j.jacl.2012.04.077.CrossrefMedlineGoogle Scholar2. 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Mirabelli M, Chiefari E, Arcidiacono B, Corigliano D, Brunetti F, Maggisano V, Russo D, Foti D and Brunetti A (2020) Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases, Nutrients, 10.3390/nu12041066, 12:4, (1066) February 14, 2017Vol 135, Issue 7 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.026278PMID: 28193798 Originally publishedFebruary 14, 2017 KeywordscholesterolEditorialshigh density lipoproteinsdietPDF download Advertisement
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