The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?
2010; Elsevier BV; Volume: 51; Issue: 8 Linguagem: Inglês
10.1194/jlr.r001610
ISSN1539-7262
AutoresMenno Vergeer, Adriaan G. Holleboom, John J.P. Kastelein, Jan Albert Kuivenhoven,
Tópico(s)Cholesterol and Lipid Metabolism
ResumoThere is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this "HDL hypothesis". In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct. There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this "HDL hypothesis". In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct. In 1951, Barr et al. (1.Barr D.P. Russ E. Eder H. Protein-lipid relationships in human plasma. II. In atherosclerosis and related conditions.Am. J. Med. 1951; 11: 480-493Abstract Full Text PDF PubMed Google Scholar) reported that plasma levels of high-density lipoprotein cholesterol (HDL-C) were reduced in patients with coronary artery disease. In 1977, Gordon et al. (2.Gordon T. Castelli W.P. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease: The Framingham study.Am. J. Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (3890) Google Scholar) subsequently showed that low HDL-C is a risk factor for coronary heart disease in the Framingham study. These important findings have given rise to a large number of diverse HDL studies over the last few decades. The numerous different and apparently unrelated beneficial effects that have since been ascribed to HDL appeal to the imagination. Because of a general consensus that HDL protects against atherosclerosis, what we shall term the HDL hypothesis, strategies have been developed to raise plasma HDL levels or to improve HDL function. However, it is increasingly questioned whether such interventions will indeed reduce the risk of atherosclerosis. This review summarizes the reported evidence that supports the HDL hypothesis. A low plasma HDL-C concentration is among the strongest, statistically independent risk factors for cardiovascular disease (CVD) (2.Gordon T. Castelli W.P. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease: The Framingham study.Am. J. Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (3890) Google Scholar). In a widely cited meta-analysis of four large studies (total number of individuals studied: 15,252), a 1 mg/dl increase of HDL-C levels was reported to be associated with a 2–3% decreased CVD risk (3.Gordon D.J. Probstfield J.L. Garrison R.J. Neaton J.D. Castelli W.P. Knoke J.D. Jacobs Jr., D.R. Bangdiwala S. Tyroler H.A. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.Circulation. 1989; 79: 8-15Crossref PubMed Google Scholar). This result provides an epidemiological argument in favor of therapeutically raising HDL-C levels. One may draw parallels with the detrimental consequences of elevated low-density lipoprotein cholesterol (LDL-C) levels and blood pressure, which have been successfully controlled through therapy, resulting in significant reductions of cardiovascular mortality and morbidity (4.Blood Pressure Lowering Treatment Trialists' CollaborationEffects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.BMJ. 2008; 336: 1121-1123Crossref PubMed Scopus (608) Google Scholar, 5.Cholesterol Treatment Trialists' (CTT) CollaboratorsEfficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). It should be noted, however, that the associations between elevated LDL-C and blood pressure and increased CVD risk reflect causal relationships, whereas such a relation between low HDL-C levels and increased CVD is not undisputed (6.Hausenloy D.J. Yellon D.M. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels.Heart. 2008; 94: 706-714Crossref PubMed Scopus (0) Google Scholar, 7.Wild S. Byrne C.D. Time to rethink high-density lipoprotein?.Heart. 2008; 94: 692-694Crossref PubMed Scopus (0) Google Scholar). This is related to the fact that HDL-C levels are influenced by many different variables that also affect CVD risk: 1) Men have on average lower HDL-C levels than women (8.Hansel B. Kontush A. Giral P. Bonnefont-Rousselot D. Chapman M.J. Bruckert E. One third of the variability in HDL-cholesterol level in a large dyslipidaemic population is predicted by age, sex and triglyceridaemia: The Paris La Pitie Study.Curr. Med. Res. Opin. 2006; 22: 1149-1160Crossref PubMed Scopus (0) Google Scholar). 2) Smokers have 14% lower HDL-C levels than nonsmokers, and this relationship appears to be dose-dependent, (9.Criqui M.H. Wallace R.B. Heiss G. Mishkel M. Schonfeld G. Jones G.T. Cigarette smoking and plasma high-density lipoprotein cholesterol. The Lipid Research Clinics Program Prevalence Study.Circulation. 1980; 62: IV70-IV76PubMed Google Scholar) whereas individuals who quit smoking show a subsequent increase in HDL-C levels (10.Hulley S.B. Cohen R. Widdowson G. Plasma high-density lipoprotein cholesterol level. Influence of risk factor intervention.JAMA. 1977; 238: 2269-2271Crossref PubMed Google Scholar). Even in individuals who acutely smoke two cigarettes, HDL-C levels drop 6 mg/dl (11.Gnasso A. Haberbosch W. Schettler G. Schmitz G. Augustin J. Acute influence of smoking on plasma lipoproteins.Klin. Wochenschr. 1984; 62: 36-42PubMed Google Scholar). 3) A recent meta-analysis of 25 studies (total number of individuals studied: 2,027) shows that programs of regular aerobic exercise increased HDL-C levels by 2.5 mg/dl on average (12.Kodama S. Tanaka S. Saito K. Shu M. Sone Y. Onitake F. Suzuki E. Shimano H. Yamamoto S. Kondo K. et al.Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis.Arch. Intern. Med. 2007; 167: 999-1008Crossref PubMed Scopus (337) Google Scholar). 4) Obesity, especially abdominal obesity, is also associated with lower HDL-C levels (13.Rashid S. Genest J. Effect of obesity on high-density lipoprotein metabolism.Obesity (Silver Spring). 2007; 15: 2875-2888Crossref PubMed Scopus (101) Google Scholar), whereas weight loss results in an elevation of HDL-C levels (14.Busetto L. Sergi G. Enzi G. Segato G. De Marchi F. Foletto M. De Luca M. Pigozzo S. Favretti F. Short-term effects of weight loss on the cardiovascular risk factors in morbidly obese patients.Obesity (Silver Spring). 2004; 12: 1256-1263Google Scholar). 5) Patients with type 2 diabetes mellitus display several lipid abnormalities of which a low HDL-C level is a prominent feature (15.Chahil T.J. Ginsberg H.N. Diabetic dyslipidemia.Endocrinol. Metab. Clin. North Am. 2006; 35: 491-510Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). 6) Metabolic syndrome, a cluster of pathologies comprising abdominal obesity, hypertension, impaired glucose tolerance, high triglycerides, and low HDL-C levels, is regarded by investigators as a single disease entity resulting from insulin resistance (16.Lann D. LeRoith D. Insulin resistance as the underlying cause for the metabolic syndrome.Med. Clin. North Am. 2007; 91: 1063-1077Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). 7) In parallel, (postprandial) hypertriglyceridemia results in low HDL-C levels, associated with an increased cholesteryl ester transfer protein (CETP) driven exchange of cholesteryl esters and triglycerides between pro-atherogenic apolipoprotein (apo)B-containing lipoproteins (VLDL and LDL) and HDL (17.Hayek T. Azrolan N. Verdery R.B. Walsh A. Chajek-Shaul T. Agellon L.B. Tall A.R. Breslow J.L. Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.J. Clin. Invest. 1993; 92: 1143-1152Crossref PubMed Google Scholar). In fact, over 50% of the patients with low HDL-C levels also present with increased fasting triglycerides. (18.Tai E.S. Emmanuel S.C. Chew S.K. Tan B.Y. Tan C.E. Isolated low HDL cholesterol: an insulin-resistant state only in the presence of fasting hypertriglyceridemia.Diabetes. 1999; 48: 1088-1092Crossref PubMed Scopus (52) Google Scholar) With this in mind, HDL-C levels may be seen as a stable reflection of disturbances in triglyceride metabolism, whereas plasma triglyceride levels themselves are subject to large inter-individual and intra-individual variability. 8) Systemic inflammation (as observed in rheumatoid arthritis and systemic lupus erythematosus), a recognized risk factor for CVD (19.van Leuven S.I. Franssen R. Kastelein J.J. Levi M. Stroes E.S.G. Tak P.P. Systemic inflammation as a risk factor for atherothrombosis.Rheumatology. 2008; 47: 3-7Crossref PubMed Scopus (0) Google Scholar), is associated with a secondary dyslipidemia characterized by low HDL-C levels (20.Khovidhunkit W. Memon R.A. Feingold K.R. Grunfeld C. Infection and inflammation-induced proatherogenic changes of lipoproteins.J. Infect. Dis. 2000; 181: S462-S472Crossref PubMed Google Scholar). 9) Finally, a low socioeconomic status is an independent predictor of low HDL-C (21.Heiss G. Haskell W. Mowery R. Criqui M.H. Brockway M. Tyroler H.A. Plasma high-density lipoprotein cholesterol and socioeconomic status. The Lipid Research Clinics Program Prevalence Study.Circulation. 1980; 62: IV108-IV115PubMed Google Scholar). Interestingly, even in baboons, socially subordinate males show 31% lower HDL-C levels than dominant males, possibly related to chronic social stress (22.Sapolsky R.M. Mott G.E. Social subordinance in wild baboons is associated with suppressed high density lipoprotein-cholesterol concentrations: the possible role of chronic social stress.Endocrinology. 1987; 121: 1605-1610Crossref PubMed Google Scholar). Thus, many different factors affect both CVD risk as well as HDL-C levels. A recent very large meta-analysis comprising 302,430 individuals has once again made clear that HDL-C is a strong predictor of cardiovascular events, even after statistical adjustment for these variables (23.Di Angelantonio E. Sarwar N. Perry P. Kaptoge S. Ray K.K. Thompson A. Wood A.M. Lewington S. Sattar N. Packard C.J. et al.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (1651) Google Scholar). Such adjustments, however, do not guarantee the absence of residual confounding (24.Becher H. The concept of residual confounding in regression models and some applications.Stat. Med. 1992; 11: 1747-1758Crossref PubMed Scopus (93) Google Scholar), and one may ask what the meaning of statistical outcomes is when the adjustments concern parameters that are intrinsically related to HDL metabolism. In addition to plain HDL-C measurements, many investigators have focused on HDL-related parameters, such as levels of apoA-I (HDL's most important structural protein), or HDL subclasses (as assessed by, e.g., nuclear magnetic resonance or 1- and 2-dimensional gel electrophoresis), and have shown that some of these parameters are superior to HDL-C in cardiovascular-risk assessment. (25.Asztalos B.F. Cupples L.A. Demissie S. Horvath K.V. Cox C.E. Batista M.C. Schaefer E.J. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 2181-2187Crossref PubMed Scopus (248) Google Scholar) Although these studies are of interest, these epidemiological relationships are subject to the same confounding variables as those concerning HDL-C itself and are therefore not fit to prove that HDL is responsible for atheroprotection. In conclusion, the epidemiological association between HDL and CVD is strong and is largely responsible for the formulation of the HDL hypothesis, but in itself does not prove a causal relationship. In line with the HDL hypothesis, HDL has been reported to exhibit many anti-atherogenic properties [for an extensive review, see (26.Kontush A. Chapman M.J. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis.Pharmacol. Rev. 2006; 58: 342-374Crossref PubMed Scopus (561) Google Scholar)] that are addressed in this section. In 1982, Fielding and Fielding (27.Fielding C.J. Fielding P.E. Cholesterol transport between cells and body fluids. Role of plasma lipoproteins and the plasma cholesterol esterification system.Med. Clin. North Am. 1982; 66: 363-373Crossref PubMed Scopus (83) Google Scholar) demonstrated that HDL can act as an acceptor of cellular cholesterol, which is proposed to constitute the first step in a hypothetical pathway that is known as reverse cholesterol transport (RCT). In its broadest sense, RCT is defined as the uptake of cholesterol from peripheral cells by lipid-poor apoA-I and HDL that is mediated by lipid transporter molecules such as ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) and scavenger receptor B-I (SR-BI), and the subsequent delivery to the liver for ultimate excretion into the feces as neutral sterols or bile acids. HDL can deliver cholesterol to the liver through hepatic SR-BI, or, alternatively, CETP shuttles cholesterol from HDL to (V)LDL, which can be taken up via the LDL receptor (LDLr) pathway. The overall RCT hypothesis, especially with respect to the relationship between plasma HDL cholesterol and fecal cholesterol excretion, has been challenged by findings in both mice and humans. For mice, it has been reported that (total body) ABCA1 deficiency, causing near complete HDL deficiency, does not affect hepatobiliary flux of cholesterol (28.Groen A.K. Bloks V.W. Bandsma R.H. Ottenhoff R. Chimini G. Kuipers F. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL.J. Clin. Invest. 2001; 108: 843-850Crossref PubMed Scopus (141) Google Scholar). Similarly, modulation of apoA-I, lecithin-cholesterol acyl transferase (LCAT; an enzyme critically involved in HDL maturation), and SR-BI, resulting in large changes in plasma HDL-C concentrations, had no effect on sterol excretion (29.Alam K. Meidell R.S. Spady D.K. Effect of up-regulating individual steps in the reverse cholesterol transport pathway on reverse cholesterol transport in normolipidemic mice.J. Biol. Chem. 2001; 276: 15641-15649Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). In addition, the infusion of apoA-I-phospholipid complexes in apoA-I knockout mice did not increase fecal sterol excretion (29.Alam K. Meidell R.S. Spady D.K. Effect of up-regulating individual steps in the reverse cholesterol transport pathway on reverse cholesterol transport in normolipidemic mice.J. Biol. Chem. 2001; 276: 15641-15649Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Thus, marked manipulation of HDL metabolism in mice apparently does not result in changes in net fecal cholesterol excretion. Another method to study whole body RCT in mice has been developed by deGoma et al. (30.deGoma E.M. deGoma R.L. Rader D.J. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches.J. Am. Coll. Cardiol. 2008; 51: 2199-2211Crossref PubMed Scopus (209) Google Scholar). In short, macrophages loaded with radiolabeled cholesterol are injected into the peritoneal cavity of mice, after which the distribution of this cholesterol in plasma, liver, and feces is quantified. These studies have provided insight into which factors control the RCT pathway in mice but have not provided data on net fecal cholesterol output. In humans, the data on HDL dependent fecal cholesterol output are equivocal. Both a negative as well as the absence of a relationship between plasma HDL-C concentrations and fecal sterol excretion have been reported (31.Miettinen T.A. Kesaniemi Y.A. Cholesterol absorption: regulation of cholesterol synthesis and elimination and within-population variations of serum cholesterol levels.Am. J. Clin. Nutr. 1989; 49: 629-635Crossref PubMed Scopus (170) Google Scholar, 32.Gylling H. Miettinen T.A. Non-cholesterol sterols, absorption and synthesis of cholesterol and apolipoprotein A-I kinetics in a Finnish lecithin-cholesterol acyltransferase deficient family.Atherosclerosis. 1992; 95: 25-33Abstract Full Text PDF PubMed Scopus (22) Google Scholar, 33.Beher W.T. Gabbard A. Norum R.A. Stradnieks S. Effect of blood high density lipoprotein cholesterol concentration on fecal steroid excretion in humans.Life Sci. 1983; 32: 2933-2937Crossref PubMed Scopus (11) Google Scholar) and a recent study in seven individuals with genetically determined low HDL-C indicated reduced fecal cholesterol output (34.El-Harchaoui K. Franssen R. Hovingh G.K. Bisoendial R.J. Stellaard F. Kuipers F. Kastelein J.J. Kuivenhoven J.A. Stroes E.S. Groen A.K. Reduced fecal sterol excretion in subjects with familial hypoalphalipoproteinemia.Atherosclerosis. 2009; 207: 614-616Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Intervention studies that increase plasma HDL-C levels also provided mixed results: the infusion of pro-apoA-I or reconstituted HDL (rHDL; apoA-I purified from human blood, reconstituted with phospholipids) was reported to result in an increase of sterol excretion (35.Eriksson M. Carlson L.A. Miettinen T.A. Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I: potential reverse cholesterol transport in humans.Circulation. 1999; 100: 594-598Crossref PubMed Google Scholar, 36.Nanjee M.N. Cooke C.J. Garvin R. Semeria F. Lewis G. Olszewski W.L. Miller N.E. Intravenous apoA-I/lecithin discs increase pre-beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans.J. Lipid Res. 2001; 42: 1586-1593Abstract Full Text Full Text PDF PubMed Google Scholar), but CETP inhibition (which blocks the exchange of cholesterol from HDL to LDL, resulting in a marked HDL-C increase as well as an LDL-C decrease) had no effect (37.Brousseau M.E. Diffenderfer M.R. Millar J.S. Nartsupha C. Asztalos B.F. Welty F.K. Wolfe M.L. Rudling M. Bjorkhem I. Angelin B. et al.Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1057-1064Crossref PubMed Scopus (208) Google Scholar). Thus, human studies have only provided little evidence that HDL-C levels correlate with fecal cholesterol output. In fact, according to cholesterol flux modeling studies by Schwartz et al. (38.Schwartz C.C. Berman M. Vlahcevic Z.R. Halloran L.G. Gregory D.H. Swell L. Multicompartmental analysis of cholesterol metabolism in man. Characterization of the hepatic bile acid and biliary cholesterol precursor sites.J. Clin. Invest. 1978; 61: 408-423Crossref PubMed Scopus (128) Google Scholar), the role of HDL in total body cholesterol homeostasis is suggested to be minimal. Studying cholesterol exchange processes from another angle, Turner and Hellerstein (39.Turner S.M. Hellerstein M.K. Emerging applications of kinetic biomarkers in preclinical and clinical drug development.Curr. Opin. Drug Discov. Devel. 2005; 8: 115-126PubMed Google Scholar) have recently developed a technique that estimates tissue cholesterol efflux by means of the steady-state isotope dilution principle. Although its value remains to be determined, a potential strength of this technique is that it may be applied in both case-control settings as well as to assess the impact of novel drugs. HDL may have its most relevant role regarding vascular protection in the initial steps of the RCT pathway. Macrophages in the vessel wall take up (oxidized) LDL, turn into foam cells, and add to a pro-inflammatory environment that promotes atherosclerotic plaque formation and ultimately plaque instability. In this context, apoA-I and HDL-mediated cholesterol efflux from lipid-laden macrophages is a conceptually attractive atheroprotective mechanism. Accordingly, the cholesterol acceptor capacity of (apoB depleted) serum, or isolated HDL has been studied as a biomarker for studies that test HDL-modulating therapies (30.deGoma E.M. deGoma R.L. Rader D.J. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches.J. Am. Coll. Cardiol. 2008; 51: 2199-2211Crossref PubMed Scopus (209) Google Scholar). Some of these studies showed promising data. For example, HDL isolated from patients after treatment with the CETP inhibitor torcetrapib was shown to be able to elicit more cholesterol efflux from cultured cholesterol-loaded cells than HDL taken from patients at baseline (40.Yvan-Charvet L. Matsuura F. Wang N. Bamberger M.J. Nguyen T. Rinninger F. Jiang X.C. Shear C.L. Tall A.R. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1132-1138Crossref PubMed Scopus (170) Google Scholar). However, the only study in humans to report on the predictive value of serum cholesterol acceptor capacity for CVD showed that those patients with a recurrent cardiovascular event were, paradoxically, characterized by a high serum cholesterol acceptor capacity (41.Chirinos J.A. Zambrano J.P. Chakko S. Schob A. Goldberg R.B. Perez G. Mendez A.J. Ability of serum to decrease cellular acylcoA:cholesterol acyl transferase activity predicts cardiovascular outcomes.Circulation. 2005; 112: 2446-2453Crossref PubMed Scopus (0) Google Scholar). The authors speculated that a high serum acceptor capacity reflects an abundance of small lipid-poor HDL particles, as a consequence of an inherent inability of these patients to saturate their serum HDL with cholesterol (41.Chirinos J.A. Zambrano J.P. Chakko S. Schob A. Goldberg R.B. Perez G. Mendez A.J. Ability of serum to decrease cellular acylcoA:cholesterol acyl transferase activity predicts cardiovascular outcomes.Circulation. 2005; 112: 2446-2453Crossref PubMed Scopus (0) Google Scholar). Although this may or may not be the correct interpretation, this finding clearly illustrates the difficulties that arise in the translation of in vitro findings to the in vivo situation. Another method to study cholesterol efflux is to assess the efflux capacity of donor cells. It is known that cellular cholesterol homeostasis is controlled by ABCA1 (42.Oram J.F. Lawn R.M. Garvin M.R. Wade D.P. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages.J. Biol. Chem. 2000; 275: 34508-34511Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar), ABCG1 (43.Wang N. Lan D. Chen W. Matsuura F. Tall A.R. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins.Proc. Natl. Acad. Sci. USA. 2004; 101: 9774-9779Crossref PubMed Scopus (820) Google Scholar), and SR-BI (44.Pagler T.A. Rhode S. Neuhofer A. Laggner H. Strobl W. Hinterndorfer C. Volf I. Pavelka M. Eckhardt E.R. van der Westhuyzen D.R. et al.SR-BI-mediated high density lipoprotein (HDL) endocytosis leads to HDL resecretion facilitating cholesterol efflux.J. Biol. Chem. 2006; 281: 11193-11204Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 45.Pirillo A. Uboldi P. Kuhn H. Catapano A.L. 15-Lipoxygenase-mediated modification of high-density lipoproteins impairs SR-BI- and ABCA1-dependent cholesterol efflux from macrophages.Biochim. Biophys. Acta. 2006; 1761: 292-300Crossref PubMed Scopus (30) Google Scholar, 46.Stangl H. Cao G. Wyne K.L. Hobbs H.H. Scavenger receptor, class B, type I-dependent stimulation of cholesterol esterification by high density lipoproteins, low density lipoproteins, and nonlipoprotein cholesterol.J. Biol. Chem. 1998; 273: 31002-31008Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 47.Ji Y. Jian B. Wang N. Sun Y. Moya Mdl L. Phillips M.C. Rothblat G.H. Swaney J.B. Tall A.R. Scavenger Receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux.J. Biol. Chem. 1997; 272: 20982-20985Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar), although a large percentage of cholesterol efflux remains unexplained (48.Wang X. Collins H.L. Ranalletta M. Fuki I.V. Billheimer J.T. Rothblat G.H. Tall A.R. Rader D.J. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo.J. Clin. Invest. 2007; 117: 2216-2224Crossref PubMed Scopus (416) Google Scholar). To date, only two studies addressed the relationship between cellular cholesterol donor capacity and atherosclerosis progression in humans. The first study showed a significant association between cholesterol efflux from human skin fibroblasts and increased carotid intima media thickness (cIMT; a surrogate endpoint for cardiovascular endpoints) in nine individuals (49.van Dam M.J. de Groot E. Clee S.M. Hovingh G.K. Roelants R. Brooks-Wilson A. Zwinderman A.H. Smit A.J. Smelt A.H. Groen A.K. et al.Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.Lancet. 2002; 359: 37-42Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). The second study, of 142 subjects undergoing coronary angiography, showed that cholesterol efflux from cultured primary macrophages to HDL and apoA-I was not different between subjects with and without significant stenosis. After adjustment for age and sex (the group with stenosis was on average 6 years older and consisted of significantly more men), cholesterol efflux to HDL became significantly lower in the stenosis group (50.Linsel-Nitschke P. Jansen H. Aherrarhou Z. Belz S. Mayer B. Huber F. Kremer W. Kalbitzer H.R. Erdmann J. Schunkert H. Macrophage cholesterol efflux correlates with lipoprotein subclass distribution and risk of obstructive coronary artery disease in patients undergoing coronary angiography.Lipids Health Dis. 2009; 8: 14Crossref PubMed Scopus (32) Google Scholar). Altogether, there is no evidence for a role of HDL in the net removal of cholesterol from the body (or vascular wall) and subsequent excretion into feces in mice, whereas evidence in humans is very scarce. To date, there are no assays to measure cholesterol efflux that have proven value in predicting cardiovascular events in humans. This reflects the inherent difficulty of finding a measure for the complex dynamics of cellular cholesterol exchange in atherosclerotic lesions. In in vitro experiments, HDL has been shown to inhibit the expression of endothelial adhesion molecules (51.Cockerill G.W. Rye K.A. Gamble J.R. Vadas M.A. Barter P.J. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1987-1994Crossref PubMed Google Scholar) and to inhibit LDL-induced monocyte transmigration (52.Navab M. Imes S.S. Hama S.Y. Hough G.P. Ross L.A. Bork R.W. Valente A.J. Berliner J.A. Drinkwater D.C. Laks H. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein.J. Clin. Invest. 1991; 88: 2039-2046Crossref PubMed Google Scholar). By blocking lipopolysaccharide activity and decreasing CD11b/CD18 upregulation, rHDL has also been shown to decrease lipopolysaccharide-induced adhesion of leukocytes to human endothelial cells (53.Moudry R. Spycher M.O. Doran J.E. Reconstituted high density lipoprotein modulates adherence of polymorphonuclear leukocytes to human endothelial cells.Shock. 1997; 7: 175-181Crossref PubMed Google Scholar). In addition, the anti-oxidative activity of HDL is typically characterized by its ability to inhibit LDL oxidation (54.Navab M. Berliner J.A. Subbanagounder G. Hama S. Lusis A.J. Castellani L.W. Reddy S. Shih D. Shi W. Watson A.D. et al.HDL and the inflammatory response induced by LDL-derived oxidized phospholipids.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 481-488Crossref PubMed Google Scholar) but it has also been shown to inhibit the formation of reactive oxygen species (55.Lee C.M. Chien C.T. Chang P.Y. Hsieh M.Y. Jui H.Y. Liau C.S. Hsu S.M
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