help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alenezi, M. Y.
Right arrow Articles by Genest, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alenezi, M. Y.
Right arrow Articles by Genest, J., Jr.
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 761-764
Copyright © 2004 by The Endocrine Society

Is the Decreased High-Density Lipoprotein Cholesterol in the Metabolic Syndrome Due to Cellular Lipid Efflux Defect?

Mohammad Y. Alenezi, Michel Marcil, David Blank, Mark Sherman and Jacques Genest, Jr.

Cardiovascular Genetics Laboratory (M.Y.A., M.M., J.G.), Division of Cardiology; Division of Clinical Biochemistry (M.Y.A., D.B.); and Division of Endocrinology (M.S.), Department of Medicine, McGill University Health Center/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada

Address all correspondence and requests for reprints to: Jacques Genest Jr., M.D., F.R.C.P.(C.), Director, Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC Canada H3A 1A1. E-mail: jacques.genest{at}muhc.mcgill.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The metabolic syndrome (MS) is associated with cardiovascular disease. The low high-density lipoprotein cholesterol (HDL-C) seen in the MS is associated with increased hepatic secretion of apolipoprotein B-containing lipoproteins. Patients with low HDL-C and abnormal cellular lipid efflux due to ABCA1 gene defects (Tangier disease) also have elevated plasma triglycerides. In the present study, we examined the cellular cholesterol and phospholipid efflux in patients with low HDL-C and features of the MS. Forty-four patients with a HDL-C below the fifth percentile for age and gender were selected. The MS was defined by a low HDL-C and at least two additional features: body mass index at least 30 kg/m2, plasma triglycerides at least 150 mg/dl, fasting glucose at least 110 mg/dl, and blood pressure at least 130/85 mm Hg. Cellular lipid efflux was examined on fibroblasts obtained from study subjects, nine normal controls and six subjects with Tangier disease. In 22 patients identified with the MS, HDL-C was 21 ± 7 mg/dl, triglyceride levels were 340 ± 157 mg/dl, and cellular cholesterol and phospholipid efflux were 107 ± 18% and 105 ± 17% of controls, respectively. No patient with the MS and low HDL-C showed a cellular lipid efflux defect. We conclude that primary cellular lipid efflux defects do not contribute to the low HDL-C frequently encountered in the MS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE METABOLIC SYNDROME (MS) is characterized by abdominal (visceral) obesity, insulin resistance and hyperglycemia, elevated blood pressure, and dyslipidemia [elevated plasma triglycerides and a decreased plasma level of high-density lipoprotein cholesterol (HDL-C)]. Because each of these features represents a continuous variable, cut-points have been set arbitrarily as diagnostic criteria. Patients with the MS are at high risk for type 2 diabetes mellitus and cardiovascular disease (1, 2, 3, 4). The modified World Health Organization (WHO) criteria define the MS (in men) as hyperinsulinemia (fasting insulin levels in the top 25% of the nondiabetic population), impaired fasting glycemia or diabetes, and the presence of at least two of the following: abdominal obesity [in the former definition, waist-hip ratio > 0.90 or body mass index (BMI) >= 30 kg/m2; and in the modified definition, waist girth >= 94 cm], dyslipidemia [serum triglycerides >= 150 mg/dl (1.7 mmol/liter); or HDL-C < 35 mg/dl (0.90 mmol/liter)], and/or blood pressure of at least 140/90 mm Hg (5, 6). The former WHO definition has been modified as proposed by the European Group for the Study of Insulin Resistance (EGIR), which recommends the use of fasting insulin levels to estimate insulin resistance and impaired fasting glucose as a substitute for impaired glucose tolerance. The EGIR also recommends lower cut-offs for blood pressure (>=140/90 mm Hg, which was >=160/90 mm Hg in the former WHO definition of the MS) that are in accordance with current WHO-International Society of Hypertension and Seventh Joint National Committee recommendations (7, 8, 9).

The National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP III) defines the MS as three or more of the following features: fasting plasma glucose, at least 110 mg/dl (6.1 mmol/liter); triglyceride level, at least 150 mg/dl (1.7 mmol/liter); HDL-C, below 40 mg/dl (1.04 mmol/liter) in men or below 50 mg/dl (1.3 mmol/liter) in women; waist circumference, greater than 102 cm in men or greater than 88 cm in women; and blood pressure at least 130/85 mm Hg (10). Low HDL-C level is one of the criteria used in the diagnosis of the MS in these different definitions. The NCEP-ATP III considers a HDL-C less than 40 mg/dl (1.04 mmol/liter) as a major risk factor for the development of coronary artery disease (10). The protective effects of HDL particles are thought to be multifactorial. HDL particles participate in reverse cholesterol transport, the mechanism by which cholesterol from extrahepatic tissues returns to the liver for excretion as biliary cholesterol. HDL has been shown also to modulate vascular endothelial function (11). In most patients, the low HDL-C is secondary to hepatic oversecretion of apolipoprotein B (apoB)-containing lipoproteins and hypertriglyceridemia (12). An inadequate transport of cellular lipids to extracellular space is associated with a rapid catabolic turnover of the lipid-poor nascent HDL particles and a low HDL-C level (13). Abnormal cellular phospholipid and cholesterol efflux has been identified as a cause of severe HDL deficiency, as seen in patients with Tangier disease (TD) and familial HDL deficiency (14). It has been shown previously (in vitro) that increased cellular lipid efflux from hepatic cells modulates the apoB secretion (15). The present study was undertaken to determine whether the low HDL-C in patients with the MS is due to cellular lipid efflux defect.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Patients were selected from the Preventive Cardiology/Lipid Clinic of the McGill University Health Centre (Montréal, Canada). The research protocol was reviewed and approved by the Ethic Committees of the institution. Signed informed consent was required for blood sampling, DNA analysis, and fibroblast cultures. Criteria for inclusion were as follows: HDL-C less than the fifth percentile for age and gender-matched subjects and a plasma triglyceride level less than 885 mg/dl (10.0 mmol/liter) (n = 44). The lipid-lowering agents were withdrawn in all study subjects for at least 4 wk. Insulin and oral hypoglycemic agents were maintained in diabetic patients, and the MS criteria were not applied in these patients (diabetic patients are classified as separate group in the present study). Patients with a known cause of HDL deficiency were excluded. Nine normolipidemic subjects and six patients with TD [mutations in ATP binding cassette A1 (ABCA1) gene] were used as controls. We have previously defined a cellular lipid efflux defect as a cellular phospholipid efflux less than 70% of normal controls (14).

Plasma lipid and apo analysis

Plasma cholesterol, triglycerides, low-density lipoprotein-C, HDL-C, apoB, and apoA-I measurements were performed using standardized methods (16).

Definition of the MS

By inclusion criterion, study patients have an HDL-C less than the fifth percentile for age and gender-matched subjects and a plasma triglyceride level below 885 mg/dl (10.0 mmol/liter). To define the MS in the present study, we used the following four parameters from NCEP-ATP III criteria: fasting plasma glucose at least 110 mg/dl (6.1 mmol/liter); triglyceride level at least 150 mg/dl (1.7 mmol/liter); HDL-C below 40 mg/dl (1.04 mmol/liter) in men or below 50 mg/dl (1.3 mmol/liter) in women; and blood pressure at least 130/85 mm Hg. Unfortunately, waist circumference was not determined, and BMI at least 30 kg/m2 has been substituted because it is one of the diagnostic criteria of the WHO definition for the MS. Patients with renal or hepatic disease were excluded.

Cell culture

Skin fibroblast cultures were established from biopsies of the anterior forearm (17). Cellular lipid efflux experiments were performed on all subjects and controls.

Cholesterol efflux

Fifty thousand cells were seeded in 12-well plates. Efflux measurements were performed as previously described (17), and the values determined as the percentage of total 3H-cholesterol released in the medium of the total (cell ± medium) measured 3H-cholesterol. Purified human apoA-I (10 µg/ml) was used as cholesterol acceptor. All experiment results were confirmed at least three times.

Phospholipid efflux

Using a similar protocol, 50,000 cells were seeded in 12-well plates. At midconfluence, the cells were labeled with 1 µCi/ml 3H-choline for 72 h. At confluence, cells were cholesterol-loaded (20 µg/ml) as above. After a 24-h equilibration period, phospholipid efflux was determined at 24 h incubation with 10 µg/ml apoA-I. Efflux medium was collected, and cellular lipids were extracted with hexane-isopropanol (3:2), whereas total phospholipids from the medium were extracted in chloroform-methanol (2:1). Efflux was determined as percentage of total 3H-phospholipids released in the medium. All results were confirmed at least twice. Because of the possibility of phospholipid hydrolysis after a prolonged incubation, phospholipid efflux was also performed after a 16-h 3H-choline labeling protocol. Final results did not differ from longer incubation (data not shown).

Statistical analysis

Values presented as mean ± SEM were compared statistically by Student’s t test. Two-tailed P values < 0.05 were considered as significantly different. Welch’s correction was applied when needed.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In the present study, we examined the cellular lipid efflux in a total of 59 subjects, including 44 subjects with a HDL-C less than the fifth percentile for age and gender match and nine normolipidemic control subjects. Six patients with TD were used as a second set of controls. Of the 44 patients, 8 had diabetes, 14 did not meet the diagnostic criteria for the MS and were classified as non-MS subjects, and 22 had the MS according to the above-mentioned definition (see Subjects and Methods). All of the characteristics of the study subjects are shown in Table 1Go.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Characteristics of study subjects

 
In the nine normal control subjects, the mean cellular cholesterol and phospholipids efflux in normal control cells were adjusted to 100%. The mean cholesterol efflux in the six control subjects with TD was 18 ± 10%, and mean phospholipid efflux was 25 ± 10% of normal controls; all of these subjects had phospholipids efflux less than 50%.

In the 14 non-MS subjects, the mean cholesterol efflux was 95 ± 30%, and the mean phospholipid efflux was 102 ± 25% of normal controls. Of the 14 subjects, two had phospholipid efflux less than 70%.

As shown in Table 1Go, the mean values of BMI, glucose, triglycerides, and the mean age are higher in patients with the MS when compared with non-MS subjects. The mean cholesterol efflux in the MS patients was 107 ± 18%, and the mean phospholipids efflux was 105 ± 17% of normal controls. No subject with features of the MS had phospholipid efflux less than 70%.

In diabetic subjects, the mean cholesterol efflux was 92 ± 18%, and the mean phospholipids efflux was 88 ± 15% of normal controls. One of eight subjects had phospholipids efflux less than 70%.

Figure 1Go represents the phospholipid efflux results in the study subjects. As seen in the figure, there is no overlap between the TD-defective efflux and the rest of the study subjects. However, there are two non-MS subjects and one diabetic patient with a phospholipid efflux value less than 70%. Linkage study at the ABCA1 gene locus was carried out in one of these subjects and in the diabetic patient. There was no segregation between the low HDL-C trait and the ABCA1 gene locus. In the second non-MS subject with a reduced phospholipid efflux, no family member was available to carry out the ABCA1 linkage analysis and exclude potential mutations in this gene.



View larger version (14K):
[in this window]
[in a new window]
  		FIG. 1. Cellular phospholipid efflux in normal control subjects (NL CTL) set at 100%, in control subjects with TD (TD CTL), in subjects with a low HDL-C but without the MS (Non MS), in subjects with low HDL-C and the MS, and in subjects with low HDL-C and diabetes.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we examined the cellular lipid efflux in 44 subjects with a low HDL-C and in 15 controls (nine normolipidemic and six TD subjects). Of these 44 subjects, 22 had features of the MS, including low HDL-C level (less than the fifth percentile). No study has previously examined the cellular lipid efflux in the MS patients with low HDL-C levels. Patients with TD and familial HDL deficiency in whom HDL-C level is low have a cellular lipid efflux defect as a result of ABCA1 gene mutations (18, 19, 20). In a series of in vitro experiments, we have shown previously that apoAI increased cellular lipid efflux from hepatic cells and decreased apoB secretion (15). This suggests a potential link between a primary abnormality of HDL particles and increased hepatic secretion of apoB-containing lipoproteins. The MS represents a cluster of cardiovascular disease risk factors and can lead to type 2 diabetes mellitus and cardiovascular disease (1, 2, 3, 4). The NCEP-ATP III recognizes the MS as a major contributor to coronary heart disease risk beyond elevated serum low-density lipoprotein (10). The MS affects a significant proportion of the U.S. population (21), and 25% of the adult citizens in Western countries suffer from this syndrome (22). Middle-aged men with the MS as defined by the NCEP-ATP III and WHO have an increased cardiovascular risk and overall mortality, even when initially without diabetes and cardiovascular disease (1). It was shown in a recent study that 51% of coronary artery disease subjects have the MS (23). There are several definitions for the MS. At present, there is no universally accepted definition for the MS, and new markers, such as C-reactive protein (24, 25) and apoB, might increase diagnostic accuracy. A low level of HDL-C is a common feature encountered in the MS. According to different literatures, 65–83% of patients with the MS had low HDL-C (26, 27, 28). About 10–15% of healthy subjects had HDL-C levels less than the 15th percentile for age and gender (29). The relationship between the low HDL-C and coronary artery disease has been shown in prospective epidemiological studies (30, 31, 32, 33). A decreased plasma level of HDL-C is a major risk factor for coronary artery disease (34), which is the major cause of death in North American society (35).

The present study shows that there is no cellular lipid efflux defect (defined as a phospholipid efflux < 70% of normal control values) in our patients with the MS and low HDL-C. By selection criteria, our patients with the MS had a severe decrease in HDL-C level (less than the fifth percentile), thereby introducing a potential selection bias. However, given our previously reported data (29), ABCA1 gene defect and cellular cholesterol efflux defect are unusual in patients with higher HDL-C. This selection bias will strengthen our conclusion that cholesterol efflux defect is not present in our study subjects with the MS. Unlike patients with TD, the low HDL-C observed in the studied patients with the MS is not due to a cellular lipid efflux defect. This study also seems to show that the MS tends to occur in older subjects, compared with subjects with low HDL-C but without the MS (56 ± 11 yr vs. 48 ± 13 yr, respectively; P = 0.0556). Moreover, there are significant differences in glucose level and BMI, which are increased in patients with the MS when compared with those without. Two non-MS subjects and one patient with diabetes showed cellular lipid efflux defect (phospholipid efflux < 70%). In two of the three subjects, there was no segregation with the ABCA1 gene locus, suggesting that other proteins or genes might be involved in the cellular lipid efflux pathway. We conclude that the low HDL-C level in our patients with the MS is not due to cellular lipid efflux defect. A low HDL-C is most likely secondary to the increased hepatic secretion of triglyceride-rich lipoproteins and increased triglycerides in HDL particles that can occur in the MS (36).


   Footnotes
 
This work was supported by an operating grant (MOP 15042) from the Canadian Institutes of Health Research and a grant from the Heart and Stroke Foundation of Québec (to J.G.). J.G. holds the McGill University-Novartis Chair in Cardiology.

Abbreviations: apo, Apolipoprotein; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; MS, metabolic syndrome; NCEP-ATP III, National Cholesterol Education Program-Adult Treatment Panel III; TD, Tangier disease.

Received August 27, 2003.

Accepted October 22, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT 2002 The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716[Abstract/Free Full Text]
  2. Trevisan M, Liu J, Bahsas FB, Menotti A 1998 Syndrome X and mortality: a population-based study. Risk Factor and Life Expectancy Research Group. Am J Epidemiol 148:958–966[Abstract/Free Full Text]
  3. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L 2001 Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683–689[Abstract/Free Full Text]
  4. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP 1992 Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 41:715–722[Abstract]
  5. Alberti KG, Zimmet PZ 1998 Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553[CrossRef][Medline]
  6. Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA 2002 Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 156:1070–1077[Abstract/Free Full Text]
  7. Balkau B, Charles MA 1999 Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 16:442–443[CrossRef][Medline]
  8. 1999 World Health Organization/International Society of Hypertension 1999 Guidelines for the management of hypertension. J Hypertens 17:151–183[Medline]
  9. Lenfant C, Chobanian AV, Jones DW, Roccella EJ 2003 Seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7): resetting the hypertension sails. Circulation 107:2993–2994[Free Full Text]
  10. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) 2001 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). JAMA 285:2486–2497[Free Full Text]
  11. O’Connell BJ, Genest Jr J 2001 High-density lipoproteins and endothelial function. Circulation 104:1978–1983[Abstract/Free Full Text]
  12. Genest Jr JJ, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, Silberman SR, Wilson PW, Salem DN, Schaefer EJ 1992 Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 85:2025–2033[Abstract/Free Full Text]
  13. Batal R, Tremblay M, Krimbou L, Mamer O, Davignon J, Genest Jr J, Cohn JS 1998 Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I. Arterioscler Thromb Vasc Biol 18:655–664[Abstract/Free Full Text]
  14. Marcil M, Bissonnette R, Vincent J, Krimbou L, Genest J 2003 Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency. Circulation 107:1366–1371[Abstract/Free Full Text]
  15. Sniderman AD, Zhang Z, Genest J, Cianflone K 2003 Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells. J Lipid Res 44:527–532[Abstract/Free Full Text]
  16. Weber M, McNicoll S, Marcil M, Connelly P, Lussier-Cacan S, Davignon J, Latour Y, Genest Jr J 1997 Metabolic factors clustering, lipoprotein cholesterol, apolipoprotein B, lipoprotein (a) and apolipoprotein E phenotypes in premature coronary artery disease in French Canadians. Can J Cardiol 13:253–260[Medline]
  17. Marcil M, Yu L, Krimbou L, Boucher B, Oram JF, Cohn JS, Genest Jr J 1999 Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency. Arterioscler Thromb Vasc Biol 19:159–169[Abstract/Free Full Text]
  18. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest Jr J, Hayden MR 1999 Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–345[CrossRef][Medline]
  19. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G 1999 The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347–351[CrossRef][Medline]
  20. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G 1999 Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355[CrossRef][Medline]
  21. Ford ES, Giles WH, Dietz WH 2002 Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359[Abstract/Free Full Text]
  22. Hauner H 2002 Insulin resistance and the metabolic syndrome: a challenge of the new millennium. Eur J Clin Nutr 56(Suppl 1):S25–S29 (Review)
  23. Solymoss BC, Bourassa MG, Lesperance J, Levesque S, Marcil M, Varga S, Campeau L 2003 Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease. Coron Artery Dis 14:207–212[CrossRef][Medline]
  24. Devaraj S, Xu DY, Jialal I 2003 C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 107:398–404[Abstract/Free Full Text]
  25. Ridker PM, Buring JE, Cook NR, Rifai N 2003 C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 107:391–397[Abstract/Free Full Text]
  26. Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V 2003 Metabolic syndrome in urban Asian Indian adults: a population study using modified ATP III criteria. Diabetes Res Clin Pract 60:199–204[CrossRef][Medline]
  27. Al Lawati JA, Mohammed AJ, Al Hinai HQ, Jousilahti P 2003 Prevalence of the metabolic syndrome among Omani adults. Diabetes Care 26:1781–1785[Abstract/Free Full Text]
  28. Solymoss BC, Bourassa MG, Campeau L, Lesperance J, Marcil M, Varga S 2003 Incidence, coronary risk profile and angiographic characteristics of prediabetic and diabetic patients in a population with ischemic heart disease. Can J Cardiol 19:1155–1160[Medline]
  29. Clee SM, Kastelein JJ, van Dam M, Marcil M, Roomp K, Zwarts KY, Collins JA, Roelants R, Tamasawa N, Stulc T, Suda T, Ceska R, Boucher B, Rondeau C, DeSouich C, Brooks-Wilson A, Molhuizen HO, Frohlich J, Genest Jr J, Hayden MR 2000 Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest 106:1263–1270[Medline]
  30. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR 1977 High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 62:707–714[CrossRef][Medline]
  31. Despres JP, Lemieux I, Dagenais GR, Cantin B, Lamarche B 2000 HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study. Atherosclerosis 153:263–272[CrossRef][Medline]
  32. Assmann G, Schulte H, von Eckardstein A, Huang Y 1996 High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 124 Suppl:S11–S120
  33. Genest Jr J, Marcil M, Denis M, Yu L 1999 High density lipoproteins in health and in disease. J Investig Med 47:31–42[Medline]
  34. Takata K, Saku K, Ohta T, Takata M, Bai H, Jimi S, Liu R, Sato H, Kajiyama G, Arakawa K 1995 A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease. Arterioscler Thromb Vasc Biol 15:1866–1874[Abstract/Free Full Text]
  35. Murray CJ, Lopez AD 1997 Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 349:1269–1276[CrossRef][Medline]
  36. Lewis GF, Rashid S, Uffelman KD, Lamarche B 2001 Mechanism of HDL lowering in insulin resistant states. Adv Exp Med Biol 498:273–277[Medline]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
R. P F Dullaart, A. K Groen, G. M Dallinga-Thie, R. de Vries, W. J Sluiter, and A. van Tol
Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol
Eur. J. Endocrinol., January 1, 2008; 158(1): 53 - 60.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
G. F. Lewis and D. J. Rader
New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport
Circ. Res., June 24, 2005; 96(12): 1221 - 1232.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alenezi, M. Y.
Right arrow Articles by Genest, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alenezi, M. Y.
Right arrow Articles by Genest, J., Jr.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals