Association Of Low-density Lipoprotein Research Articles

Abstract 17244: Association of Remnant Lipoprotein Cholesterol, Type 2 Diabetes Mellitus, and Major Adverse Cardiovascular Events: Insights From the UK Biobank

Background: Remnant lipoprotein-cholesterol (RLP-C) has emerged as a potential contributor to adverse cardiovascular events. While the association of low-density lipoprotein- cholesterol and atherosclerotic cardiovascular disease is well-established, the joint association of RLP-C and type 2 diabetes mellitus (T2DM) in driving major adverse cardiovascular events (MACE) remains less explored. Methods: We included a total of 118,004 participants from the UK Biobank with nuclear magnetic resonance-measured RLP-C. Participants were categorized into four groups based on their RLP-C levels and T2DM status: Group 1 (RLP-C below the median and no T2DM), Group 2 (RLP-C above the median and no T2DM), Group 3 (RLP-C below the median and T2DM), and Group 4 (RLP-C above the median and T2DM). Cox proportional hazards regression was employed to assess the association of these four categories with the time to incident MACE. The model was adjusted for age, sex, race, BMI, smoking, systolic blood pressure, anti-hypertensive and lipid-lowering therapy, and physical activity. Results: Our analysis revealed significant associations between RLP-C levels, T2DM, and the risk of MACE. Compared to the reference group (Group 1), Groups 2-4 had hazard ratio for the MACE outcome of 1.27 (95% CI: 1.18-1.37, p < .0001), 1.43 (95% CI: 1.29-1.59, p < .0001), and 2.04 (95% CI: 1.78-2.32, p < .0001), respectively (see Figure). Conclusion: This analysis from individuals in UK Biobank free from cardiovascular disease at baseline demonstrated a significant joint association between elevated RLP-C levels and T2DM, with the risk of major adverse cardiovascular events. Keywords: remnant lipoprotein cholesterol, type 2 diabetes mellitus, major adverse cardiovascular events, UK Biobank, nuclear magnetic resonance

Time-varying effect of postoperative cholesterol profile on long-term outcomes of isolated coronary artery bypass graft surgery

BackgroundControlling cholesterol levels is one of the primary goals of preventing atherosclerotic plaque progression in patients undergoing coronary artery bypass graft (CABG) surgery. This study aimed to investigate the impact of serum cholesterol profile at multiple time points following isolated CABG surgery on long-term patient outcomes.MethodThis retrospective cohort study was conducted on the admission and follow-up data of isolated CABG patients from the Tehran Heart Center registry between 2009 and 2016. The association of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and their ratio as an atherogenic index with major adverse cardiac and cerebrovascular events (MACCE) and all-cause mortality were evaluated using time-varying survival analysis methods.ResultA total of 18657 patients were included in this analysis. After adjusting for known confounding factors, no significant difference in all-cause mortality and MACCE was observed at different LDL levels. The incidence of acute coronary syndrome (ACS) in patients with LDL > 100 mg/dl and LDL < 50 mg/dl was significantly higher than in the control group (P-value = 0.004 and 0.04, respectively). The incidence of cerebrovascular accidents (CVA) at LDL > 100 mg/dl was also significantly higher compared to the control group (P -value = 0.033). Lower HDL levels were significantly associated with a higher MACCE (P -value < 0.001), all-cause mortality (P -value < 0.001), ACS (P -value = 0.00), and CVA (P -value = 0.014). The atherogenic index was also directly related to MACCE and all its components (all P-values < 0.001).ConclusionLDL/HDL ratio is suggested as a better marker for secondary prevention goals compared to LDL alone in patients undergoing CABG surgery.

A systematic review and meta-analyses on the effects of atorvastatin on blood pressure and heart rate.

Considering the inconsistencies in the literature on the atorvastatin effect on blood pressure (BP), we performed these meta-analyses. Through a search of the Excerpta Medica Database (EMBASE), PubMed, and Web of Science databases, 1412 articles were identified, from which 33 randomized clinical trials (RCT) and 44 pre-clinical were selected. Populations from RCT were stratified according to baseline BP and lipid levels. We performed meta-analyses of the effect of atorvastatin on systolic (SBP), diastolic and mean BP; heart rate (HR); HR variability, and baroreflex. Atorvastatin reduced SBP in the overall population (P=0.05 vs. placebo; P=0.03 vs. baseline), in normotensive and hyperlipidaemic (P=0.04 vs. placebo; P=0.0001 vs. baseline) and in hypertensive and hyperlipidaemic (P=0.02 vs. placebo; P=0.008 vs. baseline) individuals in parallel RCT, but it did not affect SBP in normotensive and normolipidaemic individuals (P=0.51 vs. placebo; P=0.4 vs. baseline). Although an effect of atorvastatin was detected in hyperlipidaemic individuals, the meta-regression coefficient for the association of low density lipoprotein (LDL)-cholesterol reduction with SBP reduction in the overall population demonstrated that SBP reduction is not dependent on the changes in LDL-cholesterol. A meta-analysis of preclinical reports demonstrated that SBP was reduced in atorvastatin-treated hypertensive and normolipidaemic rats (spontaneously hypertensive rats: P<0.00001), but not in normotensive and normolipidaemic rats (control rats: P=0.97). Atorvastatin also reduced the HR in spontaneously hypertensive rat. Atorvastatin lowers BP independent of LDL-cholesterol levels. Additional studies are needed to estimate the involvement of the autonomic nervous system in the BP-lowering effect of atorvastatin.

Association of Indices of Adiposity with Lipoprotein Sub-fractions in the general Population of Amritsar City

Elevated low density lipoprotein cholesterol levels in circulation may get deposited in coronary arteries and result in atherosclerotic plaques at an early age and act as risk factor for cardiovascular diseases. More recent and detailed anthropometric indices in addition to traditional indices were assessed in this study along with lipid profile and lipoprotein indices in urban population (n = 100) of Amritsar, Punjab. n = 48 subjects comprised the case group and n = 52 subjects the control group. Study was approved by the Institutional Ethics Committee of Guru Nanak Dev University and individual voluntary written informed consent was provided by the study group. 46% of cases were obese and lipids and lipoprotein indices were significantly higher in obese group while low density lipoprotein cholesterol and low density lipoprotein cholesterol/high density lipoprotein cholesterol also in overweight category. Factor analysis extracted the 7 components out of 23 variables with a cummulative variance of 81.45%. Females had higher central obesity, waist hip ratio, waist height ratio and body adiposity index. Pearson’s correlation analysis revealed a positive significant association of age (r = 0.363, p = 0.027), socio-economic status (r = 0.328, p = 0.023), waist hip ratio (r = 0.298, p = 0.042), waist height ratio (r = 0.864, p = 0 000) and body mass index (r = 0.794, p = 0.000) with low density lipoprotein cholesterol levels and of gender with atherogenic index (r = 0.363, p = 0.011). Also, a significant correlation of total body fat mass with atherogenic index (r = 0.286, p = 0.048) and and body roundness index with low density lipoprotein (r = 0.345, p = 0.016) was observed. Multivariate regression analysis revealed age (B = 0.318, t = 2.380, p = 0.022) and gender (B = 0.370, t = 2.687, p = 0.010) to be significant predictors of body roundness index as well as age (B = 0.139, t = 2.307, p = 0.027) of low density lipoprotein cholesterol. The highest prediction accuracy was showed by waist circumference (AUC = 0.597) and the least by a body shape index (AUC = 0.458) as revealed by Receiver Operating Characteristics analysis. A positive association of low density lipoproteins with central and general obesity, signifies that lipid metabolism gets affected by adiposity and may further affect the lipoprotein indices which are reported to be associated with atherosclerosis and coronary heart diseases.

An association of low-density lipoproteins and fibrinolysis in patients with severe aortic stenosis- valvular expression of fibrinolytic proteins

Abstract Background Aortic stenosis (AS) is associated with hyperlipidemia and hypofibrinolysis. The contribution of serum lipids to the valvular expression of fibrinolytic proteins is not known. Aims To evaluate whether fibrinolytic factors are present within stenotic aortic valves and to determine their potential associations with LDL cholesterol concentrations, their oxidized forms (oxPL-LDL), and AS severity. Methods We enrolled 75 patients with isolated severe AS aged 66±8 years (mean gradient 52 mmHg, max gradient 84 mmHg) undergoing valve replacement surgery. Aortic valve leaflets obtained from AS patients (n=30) and from age-matched healthy autopsy donors (n=3) were used to evaluate in loco the presence of plasminogen (PLG), tissue plasminogen activator (tPA), and fibrinolysis inhibitors (α2-antiplasmin and plasminogen activator inhibitor, PAI-1). PLG activity, plasma tPA and PAI-1 levels, along with cholesterol and oxPL-LDL were assayed. Clot lysis time (CLT) was performed to assess the overall fibrinolytic system activity. Results AS patients with LDL cholesterol ≥3.0 mM (n=25, 56% taking statin) compared to those with LDL cholesterol &amp;lt;3.0 mM (n=50, 86% taking statin) had higher oxPL-LDL levels (+80%, p=0.0014). Moreover, AS subjects with LDL cholesterol ≥3.0 mM, compared to those with LDL cholesterol &amp;lt;3.0 mM had longer CLT (+22.4%, p=0.0022) along with higher plasma tPA (+31.5%, p=0.004) and PAI-1 (+47.4%, p=0.01), while PLG activity tended to be higher (+10.8%, p=0.056). For the first time the valvular expression of fibrinolytic proteins was detected in AS patients, but not in healthy donors. The expression of studied proteins was observed mainly on the aortic side of the leaflets and only trace amounts were detectable in deeper layers of valves. The valve area positive for PLG was 4.4±1.8%, for tPA 1.6±0.8%, while the expression of α2-antiplasmin was 4.2±1.7% and 6.9±2.3% for PAI-1. In the whole AS group, oxPL-LDL, but not LDL cholesterol showed associations with mean (r=0.34, p=0.041) and max (r=0.3, p=0.016) gradients. Serum concentrations of LDL cholesterol correlated with CLT (r=0.42, p=0.0002), blood PLG activity (r=0.56, p=0.0012) and with tPA (r=0.43, p=0.0001) and PAI-1 (r=0.32, p=0.006) levels. Similarly, oxPL-LDL were associated with CLT, PLG activity, and tPA (r=0.34; r=0.59; r=0.47, all p&amp;lt;0.01). Valvular expression of fibrinolytic proteins did not correlate with LDL cholesterol, ox-PL-LDL or transvalvular gradients. Conclusions This study is the first to demonstrate that in AS patients hypercholesterolemia and enhanced lipid oxidation are associated with impaired systemic fibrinolysis, which supports the concept of beneficial effects of cholesterol-lowering therapy in mild-to-moderate AS. Moreover, valvular expression of fibrinolytic factors suggests that these factors are delivered with circulating blood but not synthesized de novo. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre (NCN)

Association of Low-Density Lipoprotein With All-Cause and Cause-Specific Mortality Among Us Adults

Background: To determine the association between levels of low-density lipoprotein-cholesterol (LDL-C) and all-cause and cause-specific mortality among US adults based on a prospective cohort study. Methods: All participants were included from the National Health and Nutrition Examination Survey (NHANES) 1999-2014, a survey conducted by the Centers for Disease Control and Prevention (CDC). Among 10850 individuals, 1355 (12.5%) died after an average follow-up of 5.7 years. Baseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined quantile categories with Cox regression models. Results: The association between levels of LDL-C and the risk of all-cause mortality was L shaped, with low levels associated with an increased mortality risk. The concentration of LDL-C associated with the lowest risk of all-cause mortality was 124 mg/dL (3.2mmol/L) in the overall population, and 134 mg/dL (3.4mmol/L) in individuals not receiving lipid lowering treatment. Compared with individuals with concentrations of LDL-C of 110-134 mg/dL (the 3rd quartile), the multivariable adjusted hazard ratio for all-cause mortality was 1.18 (95% confidence interval 1.01 to 1.38) for individuals with LDL-C concentrations of less than 89 mg/dL (the lowest quartile). In participants with coronary heart diseases, the conclusion was similar but the critical point was lower. Conclusions: In the general population, low levels of LDL-C were associated with an increased risk of all-cause mortality, and the lowest risk of all-cause mortality for LDL-C concentration was 124mg/dL (3.2mmol/L). The critical point was 92 mg/dL (1.04 mmol/L) in participants with coronary heart disease. Funding Information: None. Declaration of Interests: The authors have nothing to disclose regarding conflict of interest with respect to this manuscript. Ethics Approval Statement: The protocol was approved by the Institutional Review Board of the CDC and no new data was added.

0339: Estimation of small LDL level using the simple precipitation method in Tunisian coronary artery disease patients with and without type 2 diabetes

Small dense LDL particles (sdLDL), with greater suceptibility to oxydation, are well-recognized risk marker for coronary artery disease (CAD) and type 2 diabetes mellitus. The aim of the present study sought to separate sdLDL subfraction by heparin-magnesiun precipitation method and to evaluate the possible association of low-density lipoprotein (LDL) particle size CAD and type 2 diabetes mellitus. Forty eight CAD (with or without type 2 diabetes mellitus) patients and 51 apparently healthy subjects were included in this study. sdLDL-cholesterol (sdLDL-C) measured after heparin-magnesiun precipitation. LDL-Cholesterol (LDL-C) was calculated by the Friedwald formula and large, buoyant LDL-Cholesterol (lrgLDL-C) was estimated by subtraction. The prevalence of sdLDL was strongly related with the CAD risk level. However, large, buoyant LDL-C showed no significant decrease in CAD patients. LDL-C decreased significantly in CAD without diabetes (CADd-) when compared to controls. Its level significantly lower in CAD with diabetes (CADd+) patients with respect to healthy and to CADd-patients. Small density LDL-C increased significantly in coronary patients (with or without diabetes). However, lrgLDL-C was significantly decreased only in (CADd+) group compared to controls (0.73±0.02 vs 2.02±0.04; p= 0.03 respectively). A negative correlation (r=–0.22, p=0.03) between TG and sdLDL-C levels was observed when all groups are geathred, and was not found in controls and CAD patients (with or without diabetes). No correlation could be evidenced between HDL-C and sdLDL-C concentrations in all groups nor in CAD group. elevated sdLDL-C level may contribute to atherosclerosis that renforce the developement of coronaropathy. The decrease of lrgLDL seems to be attribuated to diabetes mellitus rather than to CAD.

Sa1083 Association of Low Density Lipoprotein and Sustained Virologic Response in Genotypes 2 and 3 Chronic Hepatitis C Patients Treated With Peginterferon and Ribavirin, a Single Center Study

Sa1083 Association of Low Density Lipoprotein and Sustained Virologic Response in Genotypes 2 and 3 Chronic Hepatitis C Patients Treated With Peginterferon and Ribavirin, a Single Center Study

Increased Low Density Lipoprotein and Increased Likelihood of Positive Prostate Biopsy in Black Americans

Differences in prostate cancer incidence, grade and stage at diagnosis, and survival in black vs nonblack men are well documented. Recent studies indicate that lipids may have a role in oncogenesis, including that of prostate cancer. We investigated the relationship between circulating lipids in black and nonblack patients, and newly diagnosed prostate cancer. The study population included consecutive patients who underwent prostate biopsy for increased prostate specific antigen and/or abnormal digital rectal examination at Atlanta Veterans Affairs Medical Center. Age, race, prostate specific antigen, prostate volume, body mass index, family history, high and low density lipoprotein, triglyceride and cholesterol lowering medications were included in data analysis. A total of 1,775 men with complete information were included in data analysis. A total of 521 black and 451 white men had positive biopsies. Using 100 mg/dl or less as the referent the adjusted OR reflecting the association of low density lipoprotein and prostate cancer diagnosis in black men was 1.49 (95% CI 1.04-2.13, p = 0.031), 1.51 (95% CI 0.96-2.39, p = 0.076) and 3.24 (95% CI 1.59-6.92, p = 0.002) for low density lipoprotein greater than 100 to 130, greater than 130 to 160 and greater than 160 mg/dl, respectively. Corresponding results in nonblack men showed no significant association. Increased serum low density lipoprotein is associated with an increased likelihood of prostate cancer diagnosis in black men but not in nonblack men. This association is strongest in the highest low density lipoprotein risk category. The reasons for the racial differences are unknown but may include genetic, dietary or other environmental factors.

Resistance of native and circulating modified low-density lipoproteins in human blood to association

The resistance of native and circulating modified low-density lipoproteins from human blood to spontaneous and polyethylene glycol-induced association was studied by recording light transmission fluctuations. Circulating modified low-density lipoproteins were less resistant to association than native low-density lipoproteins. Polyethylene glycol-induced association of low-density lipoproteins was irreversible. Our results suggest that atherogenic activity of circulating modified low-density lipoproteins is associated with their increased predisposition to irreversible association.

African American-white differences in lipids, lipoproteins, and apolipoproteins, by educational attainment, among middle-aged adults: the Atherosclerosis Risk in Communities Study.

Measures of socioeconomic status have been shown to be related positively to levels of high density lipoprotein (HDL) cholesterol in white men and women and negatively in African American men. However, there is little information regarding the association between educational attainment and HDL fractions or apolipoproteins. The authors examined these associations in 9,407 white and 2,664 African American men and women aged 45-64 years who participated in the Atherosclerosis Risk in Communities Study baseline survey, and they found racial differences. A positive association for HDL cholesterol, its fractions HDL2 and HDL3 cholesterol, and its associated apolipoprotein A-I was found in white men and white women, but a negative association was found in African American men, and there was no association in African American women. In whites, there was also an inverse association of low density lipoprotein (LDL) cholesterol and apolipoprotein B with educational attainment. With the exception of African American men, advanced education was associated with a more favorable cardiovascular lipid profile, which was strongest in white women. Racial differences in total cholesterol (women only), plasma triglycerides, LDL cholesterol, apolipoprotein B (women only), HDL cholesterol, HDL2 and HDL3 cholesterol, and apolipoprotein A-I were reduced at higher levels of educational attainment. Apart from triglycerides in men and HDL3 cholesterol in women, these African American-white lipid differences associated with educational attainment remained statistically significant after multivariable adjustment for lifestyle factors. Lipoprotein(a) showed no association with educational attainment. These findings confirm African American-white differences in lipids, lipoproteins, and apolipoproteins across levels of educational attainment that were not explained by conventional nondietary lifestyle variables. Understanding these differences associated with educational attainment will assist in identifying measures aimed at prevention of cardiovascular disease.

Effect of serum amyloid A on cellular affinity of low density lipoprotein.

Serum amyloid A, an apolipoprotein of high density lipoproteins, is also present to a lesser degree in low density lipoproteins and is co-localized with apolipoprotein B in atherosclerotic lesions. This study examined the effect of serum amyloid A on cellular affinity of low density lipoprotein in vitro. 125I-labelled low density lipoprotein, when loaded with recombinant serum amyloid A1 (acute phase isotype) or recombinant serum amyloid A4 (constitutive isotype), had enhanced binding to both human skin fibroblasts and a murine macrophage cell line, J774, while its degradation was slightly increased in both cells. The binding of oxidized low density lipoprotein to J774 cells was also enhanced by addition of recombinant serum amyloid A1 or serum amyloid A4, and degradation of oxidized low density lipoprotein was moderately enhanced by recombinant serum amyloid A1. The effects of recombinant serum amyloid A on cellular binding of labelled low density lipoprotein were not competed by non-labelled low density lipoprotein and were diminished in the presence of high density lipoprotein. These findings suggest that serum amyloid A in low density lipoprotein may promote association of low density lipoprotein with cells by non-specific adsorption, and high density lipoprotein may prevent such interactions by removal of serum amyloid A.

Molecular parameters that control the association of low density lipoprotein apo B-100 with chondroitin sulphate

The association of low density lipoprotein (LDL) with proteoglycans of the intima, in particular chondroitin 6-sulphate proteoglycans, may contribute to LDL accumulation during atherogenesis. We studied the interactions of apolipoprotein B-100 (apo B-100) peptide segments and model peptides with chondroitin 6-sulphate. The ability of these peptides to inhibit complex formation between LDL and chondroitin 6-sulphate was used as a measurement of the interaction. Results from earlier studies suggest that surface located segments of apo B-100 are responsible for the interaction of LDL with heparin and chondroitin sulphate-rich arterial proteoglycans. Therefore 16 hydrophilic apo B-100 peptides were selected for studies and synthesized with a peptide synthesizer. These synthetic peptides were 7 to 26 amino acids long. Four of the peptides inhibited the association of LDL with chondroitin 6-sulphate, namely apo B segments 4230–4254, 3359–3377, 3145–3157 and 2106–2121. The 3359–3377 segment was the most efficient. A common feature betweeb the interacting peptides was an excess of positively charged side chains and based on these results we synthesized nine model peptides that shared sequence characateristics with the interacting apo B-100 peptides. Five of these: RSGRKRSGK, RSSRKRSGK, RGGRKRGGK, RSRSRSRSR AND RGRGRGRGR were shown to block the LDL-chrondroitin-6-sulphate association, RSRSRSRSR being the most effective. The results suggest that the optimal association of the peptides with chrondroitin 6-sulphate is obtained with a minimal chain length of nine amino acids and a minimum of five positive charges and that flexibility in the binding region is important.

Modifications of low-density lipoprotein induced by arterial proteoglycans and chondroitin-6-sulfate

Association of low-density lipoproteins (LDL) with arterial chondroitin sulfate proteoglycans (CSPG) appears to contribute to their deposition in the extracellular intimal compartment and to its internalization by macrophages. CSPG and LDL interact by ionic bridges with formation of soluble and insoluble complexes. We studied the alterations on LDL structure induced by its association with arterial CSPG and other glycosaminoglycans (GAG). In soluble complexes, at low and physiological ionic strength, arterial CSPG and sulfated GAG modify the kinetics of apoB-100 proteolysis by trypsin. However, less marked alterations in the peptide patterns were observed with proteinase V8 and almost none with thermolysin. This is indirect evidence that the presence of CSPG and GAG modified the exposure of polar regions of apoB-100 in LDL. Competitive binding experiments with agarose-bound heparin and soluble GAG also suggest that after formation of insoluble complexes with arterial CSPG and resolubilization the exposure of Lys, Arg-rich segments of apoB-100 is increased. Results from differential scanning calorimetry and differential thermal spectrophotometry showed that the CSPG and GAG-induced modifications reduced the thermal stability of the surface and core in LDL. If present in vivo, the structural alterations of polar segments of the LDL protein moiety may influence the outcome of its alteration with the arterial mesenchyma.

Cationic polypeptides modulate in vitro association of low density lipoprotein with arterial proteoglycans, fibroblasts, and arterial tissue.

Polymers of lys (plys) and arg (parg) were found to be efficient inhibitors of the formation of complexes between low density lipoprotein (LDL) and human chondroitin-6-sulfate-rich proteoglycans. Displacement curves indicate that efficiency was dependent on molecular weight. Inclusion of alanine in the polymer up to a 1:1 molar ratio (plys,ala) has a moderate effect on displacing capacity. Poly-L-lys (plys) and poly-L-arg (parg) exhibited similar displacing ability. Inclusion of tryptophan in plys and parg diminished their effect, whereas inclusion of serine in plys,ser (3:1) improved it. Plys (18.3 kD) stimulates LDL binding to human fibroblasts. This may be due to the association of polylysine to LDL, leading to an increase in its positive charge. These more positively charged LDL may have an increased association with the negatively charged region of the apolipoprotein B/E receptor. Perfusion experiments on rabbit aortic segments were used to measure the influx of 125I-LDL into the intima and to study the effect of basic polypeptides. Plys in a 10:1 molar ratio decreased the LDL uptake by approximately 25% when added to the system together with the LDL or in experiments in which the tissue segments were pre-perfused with plys, and LDL was added after elimination of the plys. The results suggest that polycationic polypeptides, due to their strong affinity for sulfated proteoglycans, interfere with the interactions of LDL with components of the arterial extracellular matrix.

Low-Density Lipoprotein Subclass Patterns and Risk of Myocardial Infarction

The association of low-density lipoprotein (LDL) subclass patterns with coronary heart disease was investigated in a case-control study of nonfatal myocardial infarction. Subclasses of LDL were analyzed by gradient gel electrophoresis of plasma samples from 109 cases and 121 controls. The LDL subclass pattern characterized by a preponderance of small, dense LDL particles was significantly associated with a threefold increased risk of myocardial infarction, independent of age, sex, and relative weight. Plasma levels of high-density lipoprotein cholesterol were decreased, and levels of triglyceride, very low-density lipoproteins, and intermediate-density lipoproteins were increased in subjects with this LDL subclass pattern. Multivariate logistic regression analyses showed that both high-density lipoprotein cholesterol and triglyceride levels contributed to the risk associated with the small, dense LDL subclass pattern. Thus, the metabolic trait responsible for this LDL subclass pattern results in a set of interrelated lipoprotein changes that lead to increased risk of coronary heart disease.

Association of low-density lipoprotein with particulate connective tissue matrix components enhances cholesterol accumulation in cultured subendothelial cells of human aorta

Low-density lipoproteins (LDL) were incubated with elastin particles, collagenase-resistant debris isolated from human aorta, and latex beads of 1.13 μm in diameter. As a result of incubation, insoluble LDL-associates were formed. These associates, as well as LDL-heparin-fibronectin-gelatin complexes described by other workers, were added to a 7-day primary culture of enzyme-isolated cells of human aortic subendothelial intima. The culture contained a mixed cell population made up mostly of typical and modified smooth muscle cells. 24 h later, total cholesterol, phospholipid, triacylglycerol, free cholesterol and cholesteryl ester levels were measured. Addition of insoluble LDL-complexes as well as LDL-associates to culture brought about a substantial accumulation of intracellular lipids; primarily, cholesteryl esters. The total cholesterol level in cultured cells was raised 3- to 8-fold. Addition of free LDL or LDL-free particles had no effect on the content of intracellular lipids. The results obtained allow the assumption that the occurrence of the LDL-mediated accumulation of intracellular lipids is due mainly to the LDL penetration inside the cell via ‘nonspecific’ phagocytosis and not through a regulated receptor-dependent pathway.

Regulation of low density lipoprotein receptor activity in primary cultures of human hepatocytes by serum lipoproteins.

The low density lipoprotein receptor activity was measured in primary cultures of human hepatocytes. The receptor-mediated association and degradation of low density lipoprotein increased gradually up to 140 and 190%, respectively, upon incubation of the cells with increasing amounts of whole serum (up to 100%). Preincubation of the cells with low density lipoprotein resulted in a weak downregulation of the receptor-mediated association of low density lipoprotein (only 35% reduction at 100 micrograms low density lipoprotein per ml). However, preincubation with high density lipoproteins with density between 1.16 and 1.20 gm per ml (heavy high density lipoprotein) resulted in a more than 2-fold stimulation of the receptor-mediated association of low density lipoprotein. This heavy high density lipoprotein-mediated stimulation could not be antagonized by a simultaneous addition of low density lipoprotein during that preincubation. We conclude that, in primary cultures of human hepatocytes, the downregulation of the low density lipoprotein receptor activity by low density lipoprotein is weak and completely overruled by heavy high density lipoprotein. If these results for human hepatocytes in vitro hold true for hepatocytes in vivo, our results might explain why in vivo liver cells still display low density lipoprotein receptor activity notwithstanding the exposure of these cells to physiological concentrations of low density lipoprotein.