Alterations in lipid transfers to HDL associated with the presence of coronary artery disease in patients with type 2 diabetes mellitus

Cardiovascular Diabetology

Raul C Maranhão³  Roberto Kalil-Filho²  José A F Ramires²  Alexandre Segre²  Whady A Hueb²  Marilia C O Sprandel¹ 

[1] Lipid Metabolism Laboratory, Heart Institute, Medical School Hospital, University of São Paulo, São Paulo, Brazil;Clinical Cardiology Division, Heart Institute, Medical School Hospital, University of São Paulo, São Paulo, Brazil;Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil

关键词: Cholesterol;    Nanoparticles;    HDL;    High-density lipoprotein;    Lipid transfers;    Type 2 diabetes;    Coronary artery disease;   

Others  :  1222731
DOI  :  10.1186/s12933-015-0270-8

 received in 2015-05-20, accepted in 2015-08-01,  发布年份 2015

【 摘 要 】

Background

We previously showed that unesterified-cholesterol transfer to high-density lipoprotein (HDL), a crucial step in cholesterol esterification and role in reverse cholesterol transport, was diminished in non-diabetic patients with coronary artery disease (CAD). The aim was to investigate whether, in patients with type 2 diabetes mellitus (T2DM), the occurrence of CAD was also associated with alterations in lipid transfers and other parameters of plasma lipid metabolism.

Methods

Seventy-nine T2DM with CAD and 76 T2DM without CAD, confirmed by cineangiography, paired for sex, age (40–80 years), BMI and without statin use, were studied. In vitro transfer of four lipids to HDL was performed by incubating plasma of each patient with a donor emulsion containing radioactive lipids during 1 h at 37 °C. Lipids transferred to HDL were measured after chemical precipitation of non-HDL fractions and the emulsion. Results are expressed as % of total radioactivity of each lipid in HDL.

Results

In T2DM + CAD, LDL-cholesterol and apo B were higher than in T2DM. T2DM + CAD also showed diminished transfer to HDL of unesterified cholesterol (T2DM + CAD = 7.6 ± 1.2; T2DM = 8.2 ± 1.5 %, p < 0.01) and of cholesteryl-esters (4.0 ± 0.6 vs 4.3 ± 0.7, p < 0.01). Unesterified cholesterol in the non-HDL serum fraction was higher in T2DM + CAD (0.93 ± 0.20 vs 0.85 ± 0.15, p = 0.02) and CETP concentration was diminished (2.1 ± 1.0 vs 2.5 ± 1.1, p = 0.02). Lecithin-cholesterol acyltransferase activity, HDL size and lipid composition were equal.

Conclusion

Reduction in T2DM + CAD of cholesterol transfer to HDL may impair cholesterol esterification and reverse cholesterol transport and altogether with simultaneous increased plasma unesterified cholesterol may facilitate CAD development in T2DM.

【 授权许可】

   
2015 Sprandel et al.

【 参考文献 】

• [1]Pasterkamp G. Methods of accelerated atherosclerosis in diabetic patients. Heart. 2013; 99:743-749.
• [2]Leança CC, Nunes VS, Panzoldo NB, Zago VS, Parra ES, Cazita PM et al.. Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects. Cardiovasc Diabetol. 2013; 12:173. BioMed Central Full Text
• [3]Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009; 5:150-159.
• [4]Fruchart JC, Davignon J, Hermans MP, Al-Rubeaan K, Amarenco P, Assmann G et al.. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol. 2014; 13:26. BioMed Central Full Text
• [5]Yassine HN, Belopolskaya A, Schall C, Stump CS, Lau SS, Reaven PD. Enhanced cholesterol efflux to HDL through the ABCA1 transporter in hypertriglyceridemia of type 2 diabetes. Metabolism. 2014; 63:727-734.
• [6]Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977; 62:707-714.
• [7]Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD et al.. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989; 79:8-15.
• [8]Acharjee S, Boden WE, Hartigan PM, Teo KK, Maron DJ, Sedlis SP et al.. Low Levels of high density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: a post hoc analysis from the COURAGE Trial. J Am Coll Cardiol. 2013; 62:1826-1833.
• [9]Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a newtherapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev. 2006; 58:342-374.
• [10]Rosenson RS, Brewer HB, Davidson WS, Fayad ZA, Fuster V, Goldstein J et al.. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012; 125:1905-1919.
• [11]Tall A. Plasma lipid transfer proteins. Ann Rev Biochem. 1995; 64:235-257.
• [12]Siebel AL, Natoli AK, Yap FY, Carey AL, Reddy-Luthmoodoo M, Sviridov D et al.. Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion. Circ Res. 2013; 113:167-175.
• [13]Abbasi A, Dallinga-Thie GM, Dullaart RP. Phospholipid transfer protein activity and incident type 2 diabetes mellitus. Clin Chim Acta. 2015; 439:38-41.
• [14]Barter PJ, Rye KA. Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J Lipid Res. 2012; 53:1755-1766.
• [15]Low H, Hoang A, Forbes J, Thomas M, Lyons JG, Nestel P et al.. Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models. Diabetologia. 2012; 55:2513-2521.
• [16]Lo Prete AC, Dina CH, Azevedo CH, Puk CG, Lopes NH, Hueb WA et al.. In vitro simultaneous transfer of lipids to HDL in coronary artery disease and in statin treatment. Lipids. 2009; 44:917-924.
• [17]Maranhao RC, Freitas FR. HDL metabolism and atheroprotection: predictive value of lipid transfers. Adv Clin Chem. 2014; 65:1-41.
• [18]Maranhao RC, Freitas FR, Strunz CM, Santos RD, Mansur AJ, Mansur AP et al.. Lipid transfers to HDL are predictors of precocious clinical coronary heart disease. Clin Chim Acta. 2012; 413:502-505.
• [19]Hueb WA, Bellotti G, de Oliveira SA, Arie S, de Albuquerque CP, Jatene AD et al.. The Medicine, Angioplasty or Surgery Study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty or bypass surgery for single proximal left anterior descending artery stenoses. J Am Coll Cardiol. 1995; 26:1600-1605.
• [20]Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499-502.
• [21]Lima E, Maranhão RC. Rapid, simple laser-light scattering method for HDL particle size in whole plasma. Clin Chem. 2004; 50:1086-1091.
• [22]Bragdon JH, Eder HA, Gould RG, Havel RJ. Lipid nomenclature: recommendations regarding the reporting of serum lipids and lipoproteins made by the Committee on Lipid and Lipoprotein Nomenclature of the American Society for the Study of Arteriosclerosis. Circ Res. 1956; 4:129.
• [23]Marotta T, Russo BF, Ferrara LA. Triglyceride-to-HDL-cholesterol ratio and metabolic syndrome as contributors to cardiovascular risk in overweight patients. Obesity. 2010; 18:1608-1613.
• [24]Hermans MP, Ahn SA, Rousseau MF. Novel unbiased equations to calculate triglyceride-rich lipoprotein cholesterol from routine non-fasting lipids. Cardiovasc Diabetol. 2014; 13:56. BioMed Central Full Text
• [25]Seviour PW, Teal TK, Richmond W, Elkeles RS. Serum lipids, lipoproteins and macrovascular disease in non-insulin-dependent diabetics: a possible new approach to prevention. Diabet Med. 1988; 5:166-171.
• [26]Kahri J, Syvanne M, Taskinen MR. Plasma cholesteryl ester transfer protein activity in non-insulin-dependent diabetic patients with and without coronary artery disease. Metabolism. 1994; 43:1498-1502.
• [27]Frohlich J, Dobiasova M. Fractional esterification rate of cholesterol and ratio of triglycerides to HDL-cholesterol are powerful predictors of positive findings on coronary angiography. Clin Chem. 2003; 49:1873-1880.
• [28]Ng DS. The role of lecithin: cholesterol acyltransferase in the modulation of cardiometabolic risks—a clinical update and emerging insights from animal models. Biochim Biophys Acta. 2012; 1821:654-659.
• [29]Savel J, Lafitte M, Pucheu Y, Pradeau V, Tabarin A, Couffinhal T. Very low levels of HDL cholesterol and atherosclerosis, a variable relationship—a review of LCAT deficiency. Vasc Health Risk Manag. 2012; 8:357-361.
• [30]Rousset X, Shamburek R, Vaisman B, Amar M, Remaley AT. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor? Curr Atheroscler Rep. 2011; 13:249-256.
• [31]Couto RD, Dallan LA, Lisboa LA, Mesquita CH, Vinagre CG, Maranhao RC. Deposition of free cholesterol in the blood vessels of patients with coronary artery disease: a possible novel mechanism for atherogenesis. Lipids. 2007; 42:411-418.
• [32]Santos RD, Hueb W, Oliveira AA, Ramires JA, Maranhao RC. Plasma kinetics of a cholesterol-rich emulsion in subjects with or without coronary artery disease. J Lipid Res. 2003; 44:464-469.
• [33]Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K et al.. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. New Eng J Med. 2011; 364:127-135.
• [34]Triolo M, Kwakernaak AJ, Perton FG, de Vries R, Dallinga-Thie GM, Dullaart RP et al.. Low normal thyroid function enhances plasma cholesteryl ester transfer in type 2 diabetes mellitus. Atherosclerosis. 2013; 228:466-471.
• [35]Dullaart RP, de Vries R, Dallinga-Thie GM, van Tol A, Sluiter WJ. Plasma cholesteryl ester transfer protein mass and phospholipid transfer protein activity are associated with leptin in type 2 diabetes mellitus. Biochim Biophys Acta. 2007; 1771:113-118.
• [36]Inukai Y, Ito K, Hara K, Yamazaki A, Takebayashi K, Aso Y et al.. Serum cholesteryl ester transfer protein concentrations are associated with serum levels of total cholesterol, beta-lipoprotein and apoproteins in patients with type 2 diabetes mellitus. Med Princ Pract. 2007; 16:367-372.
• [37]Morton RE. Free cholesterol is a potent regulator of lipid transfer protein function. J Biol Chem. 1988; 263:12235-12241.