Small dense and desialylated low density lipoprotein in diabetic patients

Abstract

Aim: This study was undertaken to investigate the physicochemical properties of modified low density lipoprotein (LDL) in diabetes.

Methods: LDL from 10 type 1 and 10 type 2 diabetic patients, as well as LDL from 10 non-diabetic subjects, was subdivided into bound and non-bound fractions by affinity chromatography on Ricinus communis agglutinin-agarose, and further characterized by sialic acid content, hydrated density, electrophoretic mobility, and the ability to induce cholesterol deposition in cultured cells.

Results: The non-bound LDL fraction was similar to native LDL from healthy subjects, with respect to its physicochemical properties, and did not produce intracellular cholesterol accumulation. The bound LDL fraction was characterized by several alterations differentiating it from non-bound LDL, namely, significantly lowered sialic acid content (by 35-50%, compared with non-bound LDL), increased electrophoretic mobility (by 40-50%), increased hydrated density (difference in modae, 5.6-5.9 mg/mL), and smaller particle size (difference in modae, 3.8-4.9 nm). Bound LDL possessed the ability to induce a 2.1- to 2.7-fold increase in intracellular cholesterol content.

Conclusion: The results showed the presence of a dense, small, more electronegative, desialylated LDL subfraction in the blood of diabetic patients, which is in vivo modified atherogenic LDL.

Keywords

Diabetes mellitus / atherosclerosis / low density lipoprotein / desialylated LDL / small dense LDL / electronegative LDL

References

[1] Ghosh P,Vaidya A,Halperin JA.Role of complement and complement regulatory proteins in the complications of diabetes..Endocr Rev2015;36:272-88 PMCID:PMC4446516

[2] Nathan DM,Cleary P,Gubitosi-Klug R,Lorenzi G.Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions..Diabetes2013;62:3976-86 PMCID:PMC3837056

[3] Moore DJ,Kumah-Crystal YA.Mitigating micro-and macro-vascular complications of diabetes beginning in adolescence..Vasc Health Risk Manag2009;5:1015-31 PMCID:PMC2788594

[4] Aronson D.Coronary artery disease and diabetes mellitus..Heart Fail Clin2016;12:117-33

[5] Kones R.Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey..Drug Des Devel Ther2011;5:325-80 PMCID:PMC3140289

[6] Goldstein JL.A century of cholesterol and coronaries: from plaques to genes to statins..Cell2015;161:161-72 PMCID:PMC4525717

[7] Shi H,Zhong Y,Zhao X,Zhu R,Zhu J,Mao Y.Lanatoside C promotes foam cell formation and atherosclerosis..Sci Rep2016;6:20154 PMCID:PMC4731744

[8] Das A,Anderson DD,Radhakrishnan A.Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis..Elife2014;3:02882 PMCID:PMC4086274

[9] Yang H,Zhou SH.Oxidized low density lipoprotein, stem cells, and atherosclerosis..Lipids Health Dis2012;11:85 PMCID:PMC3475066

[10] Orekhov AN,Sobenin IA.Approach to reduction of blood atherogenicity..Oxid Med Cell Longev2014;2014:738679

[11] Bobryshev YV,Chistiakov DA,Orekhov AN.Macrophages and their role in atherosclerosis: pathophysiology and transcriptome analysis..Biomed Res Int2016;2016:9582430

[12] Zakiev ER,Melnichenko AA,Ivanova EA.Lipid composition of circulating multiple-modified low density lipoprotein..Lipids Health Dis2016;15:134 PMCID:PMC4995786

[13] Sobenin,Tertov VV,Bünting CE,Dedov II.Modified low density lipoprotein from diabetic patients causes cholesterol accumulation in human intimal aortic cells..Atherosclerosis1993;100:41-54

[14] Sobenin IA,Orekhov AN.Characterization of chemical composition of native and modified low density lipoprotein occurring in the blood of diabetic patients..Int Angiol1994;13:78-83

[15] Austin MA,Hennekens CH,Willett WC.Low-density lipoprotein subclass patterns and risk of myocardial infarction..JAMA1988;260:1917-21

[16] Musliner TA.Lipoprotein subspecies and risk of coronary disease..Clin Chem1988;34:B78-83

[17] Packard CJ.Small dense low-density lipoprotein and its role as an independent predictor of cardiovascular disease..Curr Opin Lipidol2006;17:412-7

[18] Ivanova EA,Orekhov AN.LDL electronegativity index: a potential novel index for predicting cardiovascular disease..Vasc Health Risk Manag2015;11:525-32 PMCID:PMC4559248

[19] Puavilai G,Sriphrapradaeng A.Diagnostic criteria for diabetes mellitus and other categories of glucose intolerance: 1997 criteria by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (ADA), 1998 WHO consultation criteria, and 1985 WHO criteria. World Health Organization..Diabetes Res Clin Pract1999;44:21-6

[20] Lindgren FT.Preparative ultracentrifugal laboratory procedures and suggestions for lipoproten analysis..In: Perkins EG, editor. Analysis of lipids and lipoproteins.1975;New YorkAmerican Oil Chemical Society205-24

[21] Tertov VV,Tonevitsky AG,Smirnov VN.Isolation of atherogenic modified (desialylated) low density lipoprotein from blood of atherosclerotic patients: separation from native lipoprotein by affinity chromatography..Biochem Biophys Res Commun1990;167:1122-7

[22] Jaakkola O,Ylä-Herttuala S.Receptor-mediated binding and degradation of subfractions of human plasma low-density lipoprotein by cultured fibroblasts..Biochim Biophys Acta1989;1005:118-22

[23] Jaakkola O,Tertov VV,Miettinen TA.Characteristics of low-density lipoprotein subfractions from patients with coronary artery disease..Coron Artery Dis1993;4:379-85

[24] Hara A.Lipid extraction of tissues with a low-toxicity solvent..Anal Biochem1978;90:420-6

[25] Siedel J,Ziegenhorn J.Reagent for enzymatic determination of serum total cholesterol with improved lipolytic efficiency..Clin Chem1983;29:1075-80

[26] Lowry OH,Farr AL.Protein measurement with the Folin phenol reagent..J Biol Chem1951;193:265-75

[27] Program Lipid Research Clinics. In: Manual of Laboratory Operations, Lipid and Lipoprotein Analysis, DHEW Publication No.. (NIH) 75-628. 2nd ed.1974;Washington, DCU. S. Government Printing Office1-81

[28] Krauss RM.Identification of multiple subclasses of plasma low density lipoproteins in normal humans..J Lipid Res1982;23:97-104

[29] Sobenin IA,Orekhov AN.Optimization of the assay for sialic acid determination in low density lipoprotein..J Lipid Res1998;39:2293-9

[30] Tsai NW,Huang CR,Chang YT,Chiang YF,Cheng BC,Kung CT,Lin YJ.Statin therapy reduces oxidized low density lipoprotein level, a risk factor for stroke outcome..Crit Care2014;18:R16 PMCID:PMC4056016

[31] Liu Y.Enhancing the contrast of ApoB to locate the surface components in the 3D density map of human LDL..J Mol Biol2011;405:274-83 PMCID:PMC3006490

[32] Aksenov DV,Skalbe TA,Tertov VV,Popov EV.Deglycosylation of apo B-containing lipoproteins increase their ability to aggregate and to promote intracellular cholesterol accumulation in vitro..Arch Physiol Biochem2008;114:349-56

[33] Nigam PK,Kumar A.Sialic acid in cardiovascular diseases..Indian J Clin Biochem2006;21:54-61 PMCID:PMC3453784

[34] Zeljkovic A,Spasojevic-Kalimanovska V,Bogavac-Stanojevic N,Spasic S.LDL and HDL subclasses in acute ischemic stroke: prediction of risk and short-term mortality..Atherosclerosis2010;210:548-54

[35] Oravec S,Krivosik M,Gruber M,Gavorník P.Lipoprotein profile in patients who survive a stroke..Neuro Endocrinol Lett2011;32:496-501

[36] Albers JJ,Fleg JL,Marcovina SM.Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial..Atherosclerosis2016;251:454-9 PMCID:PMC4983241

[37] Orekhov AN,Sobenin IA,Via DP,Gotto AMJr.Sialic acid content of human low density lipoproteins affects their interaction with cell receptors and intracellular lipid accumulation..J Lipid Res1992;33:805-17

[38] Koska J,Trenchevska O,Schwenke DC,Billheimer D,Nedelkov D.Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes..J Lipid Res2016;57:894-905 PMCID:PMC4847634