Lipid compositional differences of small, dense low-density lipoprotein particle influence its oxidative susceptibility: possible implication of increased risk of coronary artery disease in subjects with phenotype B.

An increased susceptibility of low-density lipoprotein (LDL) to lipid peroxidative modification may be a key factor in the higher risk of coronary artery disease (CAD) among subjects with phenotype B. Compositional differences in the LDL particle may also be implicated in its atherogenicity and, in particular, may be associated with varying degrees of oxidative susceptibility of LDL, although this remains unclear. We hypothesized that the oxidative susceptibility of small, dense LDL was directly influenced by its lipid composition, which may lead to an increased risk of CAD in subjects with phenotype B. To test this hypothesis, we compared the differences in lipid compositions of LDL particles from subjects with phenotype A and those with phenotype B, and investigated the direct association of lipid composition with susceptibility to lipid peroxidative modification in 102 subjects who underwent a coronary angiographic examination. Subjects with phenotype B (n = 52) had a significantly higher incidence of CAD than subjects with phenotype A (77% v 44%; P <.005). In comparing the oxidative susceptibility of LDL, the lag time was significantly reduced in subjects with phenotype B compared to phenotype A (48.7 +/- 8.6 v 41.5 +/- 5.5 minutes; P <.0001). In addition, the lag time showed a positive correlation with LDL-peak particle diameter (PPD) (r = 0.324, P <.005). Lipid composition per LDL particle was expressed as the ratio of lipid content to apolipoprotein B (apoB) content (wt/wt). Subjects with phenotype B showed a significant depletion in the contents of free-cholesterol (FC), cholesterol ester (CE), and phospholipid (PL) per particle compared to subjects with phenotype A, although there was no significant difference in the triglyceride (TG) content per LDL particle. Except for TG, the lipid content per LDL particle showed a significant positive correlation with lag time in all subjects. Moreover, increased susceptibility of small, dense LDL to lipid peroxidative modification was most strongly associated with a depleted FC content per LDL particle. In conclusion, the greater risk of CAD in subjects with phenotype B may result, in part, from increased susceptibility to lipid peroxidative modification of LDL that is depleted in lipid contents, especially FC content per LDL particle.

[1]  B. Howard,et al.  A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects , 1995, Diabetologia.

[2]  R. Krauss,et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. , 1996, JAMA.

[3]  R. Krauss,et al.  Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. , 1996, JAMA.

[4]  J. Hokanson,et al.  Compositional differences of LDL particles in normal subjects with LDL subclass phenotype A and LDL subclass phenotype B. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[5]  M. Laakso,et al.  Prospective study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women. , 1995, Circulation.

[6]  R. Krauss.  Heterogeneity of plasma low‐density lipoproteins and atherosclerosis risk , 1994, Current opinion in lipidology.

[7]  J. Jeng,et al.  Increased oxidizability of plasma low density lipoprotein from patients with coronary artery disease. , 1994, Biochimica et biophysica acta.

[8]  E. Levy,et al.  Apoprotein B structure and receptor recognition of triglyceride-rich low density lipoprotein (LDL) is modified in small LDL but not in triglyceride-rich LDL of normal size. , 1994, The Journal of biological chemistry.

[9]  J. Coresh,et al.  Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women. , 1993, Journal of lipid research.

[10]  R. Krauss,et al.  LDL Subclass Phenotypes and the Insulin Resistance Syndrome in Women , 1993, Circulation.

[11]  R. Krauss,et al.  Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. , 1993, The American journal of medicine.

[12]  U. Garbin,et al.  Predisposition to LDL oxidation in patients with and without angiographically established coronary artery disease. , 1993, Atherosclerosis.

[13]  P. Wilson,et al.  Change in LDL particle size is associated with change in plasma triglyceride concentration. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[14]  A. Hamsten,et al.  Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man , 1992, The Lancet.

[15]  A. Hamsten,et al.  Relationships of low density lipoprotein subfractions to angiographically defined coronary artery disease in young survivors of myocardial infarction. , 1991, Atherosclerosis.

[16]  J. Hendriks,et al.  Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[17]  R. Krauss,et al.  The tangled web of coronary risk factors. , 1991, The American journal of medicine.

[18]  H. Esterbauer,et al.  Role of vitamin E in preventing the oxidation of low-density lipoprotein. , 1991, The American journal of clinical nutrition.

[19]  H. Esterbauer,et al.  Endogenous antioxidants and lipoprotein oxidation. , 1990, Biochemical Society transactions.

[20]  J J Albers,et al.  Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. , 1990, The New England journal of medicine.

[21]  R. Krauss,et al.  Differences in carbohydrate content of low density lipoproteins associated with low density lipoprotein subclass patterns. , 1990, Journal of lipid research.

[22]  D. Steinberg,et al.  Low density lipoprotein rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Atkinson,et al.  Phospholipid/cholesteryl ester microemulsions containing unesterified cholesterol: model systems for low density lipoproteins. , 1990, Journal of lipid research.

[24]  H. Esterbauer,et al.  Continuous Monitoring of in Vztro Oxidation of Human Low Density Lipoprotein , 2009 .

[25]  D. Swinkels,et al.  Low density lipoprotein subfractions and relationship to other risk factors for coronary artery disease in healthy individuals. , 1989, Arteriosclerosis.

[26]  J. S. Hyde,et al.  Oxygen permeability of phosphatidylcholine--cholesterol membranes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J L Witztum,et al.  Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. , 1989, The New England journal of medicine.

[28]  W C Willett,et al.  Low-density lipoprotein subclass patterns and risk of myocardial infarction. , 1988, JAMA.

[29]  P. Wilson,et al.  Effect of Gender, Age, and Lipid Status on Low Density Lipoprotein Su bf raction Distribution: Results from the Framingham Offspring Study , 1987, Arteriosclerosis.

[30]  H. Tyroler.  Review of lipid-lowering clinical trials in relation to observational epidemiologic studies. , 1987, Circulation.

[31]  A. Sniderman,et al.  Hyperapobetalipoproteinemia in a Kindred with Familial Combined Hyperlipidemia and Familial Hypercholesterolemia , 1987, Arteriosclerosis.

[32]  R. Krauss,et al.  Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease. , 1987, American heart journal.

[33]  D. Steinberg,et al.  Essential role of phospholipase A2 activity in endothelial cell-induced modification of low density lipoprotein. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[34]  S. Shapiro,et al.  Association of coronary atherosclerosis with hyperapobetalipoproteinemia [increased protein but normal cholesterol levels in human plasma low density (beta) lipoproteins]. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[35]  W. Kannel,et al.  Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. , 1979, Annals of internal medicine.

[36]  Tokuji Kimura,et al.  REACTION OF SINGLET OXYGEN WITH CHOLESTEROL IN LIPOSOMAL MEMBRANES. EFFECT OF MEMBRANE FLUIDITY ON THE PHOTOOXIDATION OF CHOLESTEROL , 1978 .

[37]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[38]  R. Havel,et al.  The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. , 1955, The Journal of clinical investigation.

[39]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.