Restricted accessResearch articleFirst published online 2015-4
Elevated cholesteryl ester transfer protein (CETP) activity,a major determinant of the atherogenic dyslipidemia,and atherosclerotic cardiovascular disease in South Asians
Why South Asians are at increased risk of premature atherosclerotic cardiovascular diseases compared with other ethnic groups is not fully understood. Atherogenic dyslipoproteinemia – hypertriglyceridemia, elevated numbers of low-density lipoprotein (LDL) particles and low high-density lipoprotein cholesterol (HDL-C) – is more common in South Asians but the mechanisms responsible have not been explicated. Here we examined whether the circulating lipid transfer protein, cholesteryl ester transfer protein (CETP), plays a role in the pathogenesis of the atherogenic dyslipoproteinemia among South Asians.
Methods and results
CETP activity was determined by exogenous substrate assay in the serum of healthy, metabolically well-characterized individuals of South Asian and European descent (N = 244 and 238, respectively). Serum and lipoprotein lipids and apolipoproteins were measured and lipoprotein particle number and size were quantified via nuclear magnetic resonance spectroscopy. All the elements of the atherogenic dyslipoproteinemia were more severe in South Asians and CETP activity was significantly greater by 30% in South Asians compared with Europeans, adjusted for age, sex, body mass index and waist circumference (p < 0.0001). CETP activity was directly associated with serum triglycerides and inversely with HDL-C in the whole population. CETP activity was also directly related to apoB and LDL particle number. Finally, increased CETP activity was associated with pro-atherogenic reductions in HDL and LDL particle size.
Conclusions
We identified novel associations between elevated CETP activity and the triad of quantitative and qualitative lipoprotein abnormalities in the atherogenic dyslipidemia in South Asians, a major contributor of increased atherosclerotic cardiovascular diseases in South Asians.
GuptaMSinghNVermaS. South Asians and cardiovascular risk: What clinicians should know. Circulation2006; 113: e924–e929.
2.
GuptaMBristerS. Is South Asian ethnicity an independent cardiovascular risk factor?Can J Cardiol2006; 22: 193–197.
3.
JoshiPIslamSPaisP. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA2007; 297: 286–294.
4.
PatelJVCaslakeMJVyasA. Triglycerides and small dense low density lipoprotein in the discrimination of coronary heart disease risk in South Asian populations. Atherosclerosis2010; 209: 579–584.
5.
KolluriRPinedoDEdmondson-HoltA. Dyslipidemia in South Asians living in a western community. J Clin Lipidol2009; 3: 14–18.
6.
EnasEAMohanVDeepaM. The metabolic syndrome and dyslipidemia among Asian Indians: A population with high rates of diabetes and premature coronary artery disease. J Cardiometab Syndr2007; 2: 267–275.
7.
YusufSHawkenSOunpuuS. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet2004; 364: 937–952.
8.
AnandSSYusufSVuksanV. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: The Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet2000; 356: 279–284.
9.
CostandiJMeloneMZhaoA. Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling. Circ Res2011; 108: 727–742.
10.
AdielsMOlofssonSOTaskinenMR. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol2008; 28: 1225–1236.
DesprésJP. Cardiovascular disease under the influence of excess visceral fat. Crit Pathw Cardiol2007; 6(2): 51–59.
13.
FoxCSMassaroJMHoffmannU. Abdominal visceral and subcutaneous adipose tissue compartments: Association with metabolic risk factors in the Framingham Heart Study. Circulation2007; 116: 39–48.
14.
LearSAHumphriesKHKohliS. Visceral adipose tissue accumulation differs according to ethnic background: Results of the Multicultural Community Health Assessment Trial (M-CHAT). Am J Clin Nutr2007; 86: 353–359.
SnidermanADBhopalRPrabhakaranD. Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int J Epidemiol2007; 36: 220–225.
17.
AnandSSTarnopolskyMARashidS. Adipocyte hypertrophy, fatty liver and metabolic risk factors in South Asians: The Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE). PLoS One2011; 6: e22112–e22112.
18.
CanoyDCairnsBJBalkwillA. Coronary heart disease incidence in women by waist circumference within categories of body mass index. Eur J Prev Cardiol2013; 20: 759–762.
19.
Gehani AA, Al-Hinai AT, Zubaid M, et al. Association of risk factors with acute myocardial infarction in Middle Eastern countries: The INTERHEART Middle East study. Eur J Prev Cardiol 2012; 8: 1–8.
20.
DullaartRPConstantinidesAPertonFG. Plasma cholesteryl ester transfer, but not cholesterol esterification, is related to lipoprotein-associated phospholipase A2: Possible contribution to an atherogenic lipoprotein profile. J Clin Endocrinol Metab2011; 96: 1077–1084.
21.
StalenhoefAFDavidsonMHRobinsonJG. Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk. Diabetes Obes Metab2012; 14: 30–39.
22.
EbenbichlerCFLaimerMKaserS. Relationship between cholesteryl ester transfer protein and atherogenic lipoprotein profile in morbidly obese women. Arterioscler Thromb Vasc Biol2002; 22: 1465–1469.
23.
BoekholdtSMKuivenhovenJAWarehamNJ. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: The prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study. Circulation2004; 110: 1418–1423.
24.
CuchelMRaderDJ. Is the cholesteryl ester transfer protein proatherogenic or antiatherogenic in humans?J Am Coll Cardiol2007; 50: 1956–1957.
25.
MannCJYenFTGrantAM. Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia. J Clin Invest1991; 88: 2059–2066.
26.
BorggreveSEDe VriesRDullaartRP. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: Role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. Eur J Clin Invest2003; 33: 1051–1069.
27.
ChapmanMJ. Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. Pharmacol Ther2006; 111: 893–908.
28.
RashidSUffelmanKDLewisGF. The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states. J Diabetes Complications2002; 16: 24–28.
29.
BarterPJBrewerHB JrChapmanMJ. Cholesteryl ester transfer protein: A novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol2003; 23: 160–167.
30.
RashidSBarrettPHUffelmanKD. Lipolytically modified triglyceride-enriched HDLs are rapidly cleared from the circulation. Arterioscler Thromb Vasc Biol2002; 22: 483–487.
31.
RashidSWatanabeTSakaueT. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: The combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem2003; 36: 421–429.
32.
BarterPJKasteleinJJ. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol2006; 47: 492–499.
33.
KeeblerMESandersCLSurtiA. Association of blood lipids with common DNA sequence variants at 19 genetic loci in the multiethnic United States National Health and Nutrition Examination Survey III. Circ Cardiovasc Genet2009; 2: 238–243.
34.
TalmudPJDrenosFShahS. Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. Am J Hum Genet2009; 85: 628–642.
35.
KraussRMWojnooskiKOrrJ. Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res2012; 53: 540–547.
36.
DanskyHMBloomfieldDGibbonsP. Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia. Am Heart J2011; 162: 708–716.
37.
CannonCPShahSDanskyHM. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med2010; 363: 2406–2415.
38.
NichollsSJBrewerHBKasteleinJJ. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: A randomized controlled trial. JAMA2011; 306(19): 2099–2109.
39.
MackeyRHGreenlandPGoffDC Jr. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol2012; 60: 508–516.
40.
ParishSOfferAClarkeR. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation2012; 125: 2469–2478.
41.
ChapmanMJLeGWGuerinM. Cholesteryl ester transfer protein: At the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J2010; 31: 149–164.
42.
ChapmanMJGuerinMBruckertE. Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches. Eur Heart J1998; 19(Suppl. A): A24–A30.
43.
GuerinMLe GoffWLasselTS. Proatherogenic role of elevated CE transfer from HDL to VLDL(1) and dense LDL in type 2 diabetes: Impact of the degree of triglyceridemia. Arterioscler Thromb Vasc Biol2001; 21: 282–288.
44.
RashidSTrinhDKUffelmanKD. Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I. Circulation2003; 107: 3066–3072.
45.
ColletXTallARSerajuddinH. Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I. J Lipid Res1999; 40: 1185–1193.
46.
XiaoCWatanabeTZhangY. Enhanced cellular uptake of remnant high-density lipoprotein particles: A mechanism for high-density lipoprotein lowering in insulin resistance and hypertriglyceridemia. Circ Res2008; 103: 159–166.
47.
LamarcheBUffelmanKDCarpentierA. Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men. J Clin Invest1999; 103: 1191–1199.
KontushAChapmanMJ. Antiatherogenic function of HDL particle subpopulations: Focus on antioxidative activities. Curr Opin Lipidol2010; 21: 312–318.
50.
BerneisKKKraussRM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res2002; 43: 1363–1379.
51.
YounisNSharmaRSoranH. Glycation as an atherogenic modification of LDL. Curr Opin Lipidol2008; 19: 378–384.
52.
YusufSReddySOunpuuS. Global burden of cardiovascular diseases: Part II: Variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation2001; 104: 2855–2864.
53.
LearSATomaMBirminghamCL. Modification of the relationship between simple anthropometric indices and risk factors by ethnic background. Metabolism2003; 52: 1295–1301.
54.
FranssenRMonajemiHStroesES. Obesity and dyslipidemia. Med Clin North Am2011; 95: 893–902.
55.
BambaVRaderDJ. Obesity and atherogenic dyslipidemia. Gastroenterology2007; 132: 2181–2190.
56.
TanGDOlivecronaGVidalH. Insulin sensitisation affects lipoprotein lipase transport in type 2 diabetes: Role of adipose tissue and skeletal muscle in response to rosiglitazone. Diabetologia2006; 49: 2412–2418.
57.
RashidSUffelmanKDBarrettPH. Effect of atorvastatin on high-density lipoprotein apolipoprotein A‐I production and clearance in the New Zealand white rabbit. Circulation2002; 106: 2955–2960.
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