LDL apoB Research Articles

Oxidation and uptake of LDL by monocyte-derived macrophages from blood of patients with IHD

The main goal of this study was to test our hypothesis that monocyte-derived macrophages of patients with ischemic heart disease (IHD, MPIHD) are in vivo prestimulated (primed) or stimulated cells. Their capacity for LDL oxidation and uptake exceeds that of macrophages from healthy donors (MPN). Monocytes were isolated from blood of 18 healthy donors and 25 IHD patients and LDL preparations were obtained from plasma of 16 healthy donors (LDLN) and 15 patients with familial hypercholesterolemia (LDLH). Aerobic incubation of LDLN or LDLH with MPIHD resulted in earlier accumulation (by 1 h) of TBARS in LDL, earlier aggregation of LDL (1 h vs 3 h in the case of MPN), more pronounced LDL apoB fragmentation as well as increased LDL uptake with the increase in accumulation of total cholesterol (TCh; by 1.8–2.1-fold, p < 0.05–0.01) and the decrease in cell viability compared with MPN (p < 0.01). MPIHD and MPN exhibited more effective oxidation and uptake of LDLH than LDLN and in most tests this capacity (to oxidize and uptake LDL) increased under hypoxic conditions. These results demonstrate that macrophages of IHD patients are in vivo stimulated cells and that this stimulation, especially in combination with hypercholesterolemic LDL and local or generalized hypoxia, represent serious predisposition for onset or progression of atherosclerosis in IHD patients. The express test model based on MPIHD may be used for estimation of monocyte/macrophage stimulation in IHD patients as well as for optimization of drug therapy and screening new antiatherosclerotic and antiischemic drugs.

Potent and Selective PPAR-α Agonist LY518674 Upregulates Both ApoA-I Production and Catabolism in Human Subjects With the Metabolic Syndrome

The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (-38%, P=0.002) and triglyceride (-23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (-12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II. Activation of PPAR-alpha with LY518674 (100 microg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.

Associations of alcohol consumption with blood pressure, lipoproteins, and subclinical inflammation among Turks

Gender-related impact of alcohol consumption on blood pressure (BP), serum lipoprotein profile, and C-reactive protein (CRP) concentrations was evaluated prospectively. Alcohol drinking status was assessed as abstainers and categories of light, moderate, and heavy (daily >40 ml ethanol) intake. Mean age of the 3,443 men and women who were followed up for a mean of 7.4 years was 47.6 ± 12 years. In each multivariable linear or logistic regression analysis, alcohol drinking status was adjusted for age, sex, smoking status, and physical activity. Among men, drinking was significantly associated positively with low-density lipo protein (LDL) cholesterol, apolipoprotein (apo) B, systolic and diastolic BP, and with CRP in a log-linear manner exhibiting features of a threshold at heavy drinking. With respect to response of serum triglycerides to light-to-moderate drinking, whereas men exhibited a significant increase, women exhibited a decline ( P < .05). Lower BPs ( P < .03) and CRP levels ( P = .032) were observed in female drinkers than abstainers and, as distinct from men, no increases in LDL cholesterol and apoB were noted. Heavy drinking tended to protect the sexes against the risk of developing low high-density lipoprotein cholesterol levels in prospective multi adjusted analyses. Sex modulates response of cardiometabolic risk variables to moderate alcohol consumption among Turks. Only women respond with lower triglycerides and CRP, whereas men show a log-linear positive association of drinking categories with BP, LDL cholesterol, apoB, and CRP.

The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients

Introduction Fasting and postprandial hypertriglyceridemia are essential features of metabolic syndrome. Statins decrease fasting lipid levels but fail to reduce fat load induced hypertriglyceridemia. We established whether ezetimibe combined with simvastatin differently influences post fat load lipid levels and lipoprotein composition as compared to simvastatin 80 mg monotherapy in obese male metabolic syndrome patients. Methods Prospective, randomized, double blind, crossover trial. Male obese metabolic syndrome (ATPIII) patients ( n = 19) were treated with simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg for 6 weeks. At the start of the study and after each treatment period oral fat loading tests were performed. Lipoprotein fractions (triglyceride-rich lipoproteins (TRL), IDL, LDL, and HDL) were isolated by density gradient ultracentrifugation. Postprandial changes in lipid levels were integrated as areas under the curve (AUCs). Results Fasting LDL-C, RLP-C and triglycerides were lowered equally by both simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg. Also postprandial plasma triglyceride levels (net AUC-TG) were equally lowered after both treatments (5.16 ± 0.50 mmol h/l after simvastatin/ezetimibe 10 mg/10 mg and 6.09 ± 0.71 mmol h/l after simvastatin 80 mg) compared to fat loading without treatment (6.64 ± 0.86 mmol h/l). In addition, triglyceride-content in lipoprotein fractions after fat load (net AUCs) were also equally reduced after both treatments. Similarly, TRL. IDL and LDL cholesterol and apoB concentrations were equally affected by both treatment regimens, leading to a reduced number of circulating particles, in both conditions. However the composition of these particles remained the same. Conclusion Simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg were equally effective in reducing fasting and post fat load plasma lipid, and lipoprotein concentrations and lipoprotein composition in obese metabolic syndrome patients.

Differential effect of fenofibrate and atorvastatin on in vivo kinetics of apolipoproteins B-100 and B-48 in subjects with type 2 diabetes mellitus with marked hypertriglyceridemia

The specific impact of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors and fibrates on the in vivo metabolism of apolipoprotein (apo) B has not been systematically investigated in patients with type 2 diabetes mellitus with high plasma triglyceride (TG) levels. Therefore, the objective of this 2-group parallel study was to examine the differential effects of a 6-week treatment with atorvastatin or fenofibrate on in vivo kinetics of apo B-48 and B-100 in men with type 2 diabetes mellitus with marked hypertriglyceridemia. Apolipoprotein B kinetics were assessed at baseline and at the end of the intervention using a primed constant infusion of [5,5,5-D 3]- l-leucine for 12 hours in the fed state. Fenofibrate significantly decreased plasma TG levels with no significant change in plasma low-density lipoprotein cholesterol (LDL-C) and apo B levels. On the other hand, atorvastatin significantly reduced plasma levels of TG, LDL-C, and apo B. After treatment with fenofibrate, very low-density lipoprotein (VLDL) apo B-100 pool size (PS) was decreased because of an increase in the fractional catabolic rate (FCR) of VLDL apo B-100. No significant change was observed in the kinetics of LDL apo B-100. Moreover, fenofibrate significantly decreased TG-rich lipoprotein (TRL) apo B-48 PS because of a significant increase in TRL apo B-48 FCR. After treatment with atorvastatin, VLDL and IDL apo B-100 PSs were significantly decreased because of significant elevations in the FCR of these subfractions. Low-density lipoprotein apo B-100 PS was significantly lowered because of a tendency toward decreased LDL apo B-100 production rate (PR). Finally, atorvastatin reduced TRL apo B-48 PS because of a significant decrease in the PR of this subfraction. These results indicate that fenofibrate increases TRL apo B-48 as well as VLDL apo B-100 clearance in men with type 2 diabetes mellitus with marked hypertriglyceridemia, whereas atorvastatin increases both VLDL and IDL apo B-100 clearance and decreases TRL apo B-48 and LDL apo B-100 PR.

Use of the TLX ultracentrifuge for the isolation of different density lipoproteins and effects of freeze/thawing of human plasma before ultracentrifugation

Isolation of different density lipoproteins by ultracentrifugation can require lengthy centrifugation times and freeze/thawing of plasma may influence recovery. We isolated a range of lipoproteins using a preparative ultracentrifuge and the TLX micro-ultracentrifuge and determined the effect of freeze/thawing of plasma beforehand. In fresh plasma, there was no significant difference in results for small-dense low-density lipoprotein apolipoprotein B (LDL apoB) (density >1.044 g/mL) or cholesterol at density >1.006 g/mL. Freeze/thawing had no effect on closely correlated results for small-dense LDL apoB (r=0.85; p<0.0001) or high-density lipoprotein (r=0.93; p<0.0001). The TLX micro-ultracentrifuge is a reliable alternative to the preparative ultracentrifuge and freeze/thawing has only a small effect on small-dense LDL apoB or high-density lipoprotein cholesterol.

Abstract 3481: A Prospective Comparison of NMR-Measured LDL Particle Number, Apolipoprotein B100, and Standard Lipids with Incident CHD in 27,673 Initially Healthy Women

Background While ATP-III recommends measurement of total and HDL cholesterol (HDL-C) as part of coronary risk assessment, measurement of LDL particle number (LDL-P) is not currently recommended. Methods and Results In a prospective cohort of 27,673 initially healthy women, baseline LDL-P was measured by proton nuclear magnetic resonance spectroscopy, apolipoprotein B100 (ApoB) was measured using an immunoturbidimetric assay, and standard lipids were directly measured. LDL-P correlated with LDL cholesterol (LDL-C; r=0.62), ApoB (0.84), non HDL-C (0.74), and total:HDL-C ratio (0.80). During a mean follow-up of 11 years, 668 incident coronary heart disease (CHD) events occurred. Using the lowest quintile as the reference, and adjusting for age, smoking, blood pressure, diabetes, menopause, hormone use, and body mass index, the association of LDL-P with CHD was stronger than LDL-C (Table ), and comparable in magnitude to ApoB, non HDL-C and total:HDL-C ratio. In a subgroup analysis of women with LDL-C&lt;100 mg/dL, elevations in LDL-P, ApoB, non HDL-C, or total:HDL-C ratio were all separately associated with higher CHD risk (P&lt;0.001 for all). Both LDL-P and ApoB remained associated with CHD after additionally adjusting for total cholesterol, HDL-C, and triglycerides (hazard ratios for top vs bottom quintile: 2.03 [95% CI 1.27–3.24] for LDL-P, and 3.08 [95% CI 1.92– 4.93] for ApoB) overall, and similarly in women with LDL-C&lt;100 mg/dL (2.77 [95%CI 1.05–7.29] for LDL-P and 2.62 [95%CI 0.97–7.05] for ApoB). Conclusions In this large-scale prospective cohort, elevations in NMR-measured LDL particle number were significantly associated with incident CHD, with a magnitude of risk not substantially different from ApoB, non HDL-C, or total:HDL-C ratio. Among women with LDL-C &lt;100mg/dL, elevations in LDL-P, ApoB, non HDL-C, and total:HDL-C ratio all carried higher CHD risk. Risk Factor-Adjusted Hazard Ratios for Incident CHD

Effect of Weight Loss on LDL and HDL Kinetics in the Metabolic Syndrome

The purpose of this study was to examine the effect of weight loss on LDL and HDL kinetics and plasma retinol-binding protein-4 (RBP-4) and adiponectin levels in men with the metabolic syndrome. LDL apolipoprotein (apo)B-100 and HDL apoA-I kinetics were studied in 35 obese men with the metabolic syndrome at the start and end of a 16-week intervention trial of a hypocaloric, low-fat diet (n = 20) versus a weight maintenance diet (n = 15) using a stable isotope technique and multicompartmental modeling. Consumption of the low-fat diet produced significant reductions (P < 0.01) in BMI, abdominal fat compartments, and homeostasis model assessment score compared with weight maintenance. These were associated with a significant increase in adiponectin and a fall in plasma RBP-4, triglycerides, LDL cholesterol, and LDL apoB-100 concentration (P < 0.05). Weight loss significantly increased the catabolism of LDL apoB-100 (+27%, P < 0.05) but did not affect production; it also decreased both the catabolic (-13%) and production (-13%) rates of HDL apoA-I (P < 0.05), thereby not altering plasma HDL apoA-I or HDL cholesterol concentrations. VLDL apoB-100 production fell significantly with weight loss (P < 0.05). The increase in LDL catabolism was inversely correlated with the fall in RBP-4 (r = -0.54, P < 0.05) and the decrease in HDL catabolism with the rise in adiponectin (r = -0.56, P < 0.01). In obese men with metabolic syndrome, weight loss with a low-fat diet decreases the plasma LDL apoB-100 concentration by increasing the catabolism of LDL apoB-100; weight loss also delays the catabolism of HDL apoA-I with a concomitant reduction in the secretion of HDL apoA-I. These effects of weight loss could partly involve changes in RBP-4 and adiponectin levels.

Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, atorvastatin 20 mg/day was associated with significant reductions in TRL, IDL, and LDL apoB-100 pool size as a result of significant increases in fractional catabolic rate (FCR) without changes in production rate (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. ApoB-48 pool size was reduced significantly by both atorvastatin doses, and this reduction was associated with nonsignificant increases in FCR. The lathosterol-campesterol ratio was decreased by atorvastatin treatment, and changes in this ratio were inversely correlated with changes in TRL apoB-100 and apoB-48 PR. No significant effect on apoA-I kinetics was observed at either dose of atorvastatin. Our data indicate that atorvastatin reduces apoB-100- and apoB-48-containing lipoproteins by increasing their catabolism and has a dose-dependent effect on LDL apoB-100 kinetics. Atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.

Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes

Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n = 11) and nondiabetic controls (n = 13) using a primed-constant infusion of l-[5,5,5-D(3)]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these subfractions.

The HMG-CoA Reductase Inhibitor Cerivastatin Lowers Advanced Glycation End Products in Patients with Type 2 Diabetes

Although the association between type 2 diabetes mellitus (DM) and cardiovascular diseases is well-documented, current knowledge regarding reasons for the increased prevalence of atherosclerosis in DM is incomplete. Advanced glycosylation end-products (AGE) may play an important role in the development of atherosclerosis in diabetic patients. We examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM. The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL. Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. Here we report on the effect of cerivastatin on the concentration of AGE-CML. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL. Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21% ( P=0,005; compared to -7,5% in the placebo group). The effect on AGE-CML was correlated with the reduction in LDL cholesterol (r=0.355, P=0.003) and LDL apoB (r=0.239, P=0.05). In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed in our study may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia.

LDL Cholesteryl Oleate

Cholesteryl esters (CE) are synthesized by 2 enzymes, lecithin:cholesterol acyltransferase (LCAT) and acylCoA:cholesterol acyltransferase (ACAT). LCAT functions in the plasma and forms CE in HDL by transferring polyunsaturated fatty acid from phosphatidylcholine to cholesterol. ACAT, which functions intracellularly, uses fatty acid from acylCoA and forms CE enriched in monounsaturated fatty acid. Two isoforms of ACAT are expressed.1 ACAT1 is present in many tissues and produces the CE that are stored intracellularly, whereas ACAT2 is expressed in the intestine and liver and produces the CE that are secreted in chylomicrons and VLDL.2 See page 1396 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Bell et al report that ACAT2 gene deletion prevents hypercholesterolemia and atherosclerosis induced by diets containing 10% saturated or monounsaturated fat in a murine model of high LDL apoB100 only, LDL receptor-deleted (LDLr−/−) mice.3 These mice also had larger LDL particle size and hypertriglyceridemia. They attribute the protection of ACAT2 deficiency to a decrease in LDL particles enriched in CE derived from oleate (monounsaturated). When the diet contains large amounts of monounsaturated fats, ACAT2 activity appears to favor production of VLDL particles containing an excessive amount of cholesteryl oleate,4 and these monounsaturated CE remain associated with the lipoprotein particle when it undergoes conversion to LDL. These findings remind us that CE synthesized in the liver can be a source of CE for LDL, a fact that tends to be overlooked because of the current emphasis on the role of the reverse cholesterol transport pathway and cholesteryl ester transport protein (CETP) in supplying CE to VLDL and ultimately LDL. The Figure illustrates how LCAT, CETP, and ACAT2 function to supply monounsaturated and polyunsaturated CE that can accumulate in LDL. A schematic summary of the pathways that provide cholesteryl esters (CE) for incorporation …

Dose-dependent effect of rosuvastatin on apolipoprotein B-100 kinetics in the metabolic syndrome

In a randomized, double-blind, crossover trial of 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week placebo wash-outs between treatments, the dose-dependent effect of rosuvastatin on apolipoprotein (apo) B-100 kinetics in metabolic syndrome subjects were studied. Compared with placebo, there was a significant dose-dependent decrease with rosuvastatin in plasma cholesterol, triglycerides, LDL cholesterol, apoB and apoC-III concentrations and in the apoB/apoA-I ratio, lathosterol:cholesterol ratio, HDL cholesterol concentration and campesterol:cholesterol ratio also increased significantly. Rosuvastatin significantly increased the fractional catabolic rates (FCR) of very-low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and LDL-apoB and decreased the corresponding pool sizes, with evidence of a dose-related effect. LDL apoB production rate (PR) fell significantly with rosuvastatin 40 mg/day with no change in VLDL and IDL-apoB PR. Changes in triglycerides were significantly correlated with changes in VLDL apoB FCR and apoC-III concentration, and changes in lathosterol:cholesterol ratio were correlated with changes in LDL apoB FCR, the associations being more significant with the higher dose of rosuvastatin. In the metabolic syndrome, rosuvastatin decreases the plasma concentration of apoB-containing lipoproteins by a dose-dependent mechanism that increases their rates of catabolism. Higher dose rosuvastatin may also decrease LDL apoB production. The findings provide a dose-related mechanism for the benefits of rosuvastatin on cardiovascular disease in the metabolic syndrome.

The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin

The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMG-CoA reductase inhibitor decreases cholesterol absorption and synthesis. In clinical trials, ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. The molecular mechanism for this enhanced efficacy has not been defined. Apolipoprotein B-100 (apoB-100) kinetics were determined in miniature pigs treated with ezetimibe (0.1 mg/kg/day), ezetimibe plus simvastatin (10 mg/kg/day), or placebo (n = 7/group). Ezetimibe decreased cholesterol absorption (-79%) and plasma phytosterols (-91%), which were not affected further by simvastatin. Ezetimibe increased plasma lathosterol (+65%), which was prevented by addition of simvastatin. The combination decreased total cholesterol (-35%) and LDL-cholesterol (-47%). VLDL apoB pool size decreased 26%, due to a 35% decrease in VLDL apoB production. LDL apoB pool size decreased 34% due to an 81% increase in the fractional catabolic rate, both of which were significantly greater than monotherapy. Combination treatment decreased hepatic microsomal cholesterol (-29%) and cholesteryl ester (-65%) and increased LDL receptor (LDLR) expression by 240%. The combination increased NPC1L1 expression in liver and intestine, consistent with increased SREBP2 expression. Ezetimibe plus simvastatin decreases VLDL and LDL apoB-100 concentrations through reduced VLDL production and upregulation of LDLR-mediated LDL clearance.

Acute phase proteins and oxidised low-density lipoprotein in association with ischemic stroke subtype, severity and outcome

Objectives: The goal of our study was to investigate the associations of oxidized LDL (apoB100 aldehyde-modified form) and acute phase proteins (fibrinogen, CRP) with acute ischemic stroke severity and outcome.Materials and Methods: The study included 61 ischemic stroke patients and 64 controls. Strokes were subtyped according to TOAST criteria, the severity and outcome of stroke (at 1 year) were measured.Results: The mean triglyceride, fibrinogen, CRP and glucose values were significantly higher among cases. The median oxLDL value for patients with large artery atherosclerosis (LAA) type of stroke was significantly higher than for other subtypes. The oxLDL values did not correlate with age, stroke severity and outcome.Conclusions: Inflammatory markers (fibrinogen and CRP) predicted the stroke severity and outcome whereas elevation of oxLDL levels did not. Our data refer to possibility that there may exist some links between the LAA subtype of stroke and elevated oxLDL (apoB100 aldehyde-modified form).

Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol

We studied the relationship of apolipoprotein E (apoE) isoforms and coronary artery disease (CAD) in 224 African Americans and 326 Caucasians undergoing diagnostic coronary angiography. The presence of CAD was defined as >50% stenosis in at least one artery. ApoE allele frequencies were 0.12, 0.62, and 0.26 for epsilon 2, epsilon 3, and epsilon 4, respectively, in African Americans and 0.08, 0.78, and 0.14 for epsilon 2, epsilon 3, and epsilon 4, respectively, in Caucasians. Among African Americans, CAD was present in 9 of 34 epsilon 2 carriers (26%), significantly smaller (P < 0.05) in proportion compared with 39 of 82 epsilon 3 carriers and 43 of 92 epsilon 4 carriers (48% and 47%, respectively), suggesting a protective effect of the epsilon 2 allele. No such difference was seen in Caucasians. In African Americans but not Caucasians, LDL cholesterol was lower in epsilon 2 carriers than in epsilon 3 and epsilon 4 carriers (106 vs. 127 and 134 mg/dl, respectively; P < 0.005). After adjusting for lipid levels, the association between apoE2 and CAD was no longer significant. Thus, the protective effect of apoE2 seen in African Americans could be explained by a favorable lipid profile in epsilon 2 carriers, whereas in Caucasians, the absence of such a protective effect could be attributable to the lack of effect of apoE2 on the lipid profile.

Apolipoprotein C-III isoforms: kinetics and relative implication in lipid metabolism

Apolipoprotein C-III (apoC-III) production rate (PR) is strongly correlated with plasma triglyceride (TG) levels. ApoC-III exists in three different isoforms, according to the sialylation degree of the protein. We investigated the kinetics and respective role of each apoC-III isoform in modulating intravascular lipid/lipoprotein metabolism. ApoC-III kinetics were measured in a sample of 18 healthy men [mean age (+/-SD) 42.1 +/- 9.5 years, body mass index 29.8 +/- 4.6 kg/m2] using a primed-constant infusion of l-(5,5,5-D3) leucine for 12 h. Mono-sialylated and di-sialylated apoC-III (apo-CIII1 and apoC-III2) exhibited similar PRs (means +/- SD, 1.22 +/- 0.49 mg/kg/day vs. 1.15 +/- 0.59 mg/kg/day, respectively) and similar fractional catabolic rates (FCRs) (0.51 +/- 0.13 pool/day vs. 0.61 +/- 0.24 pool/day, respectively). Nonsialylated apoC-III (apoC-III0) had an 80% lower PR (0.25 +/- 0.12 mg/kg/day) and a 60% lower FCR (0.21 +/- 0.07 pool/day) (P < 0.0001 for comparison with CIII1 and CIII2 isoforms). The PRs of apoC-III1 and apoC-III2 were more strongly correlated with plasma TG levels (r > 0.8, P < 0.0001) than was apoC-III0 PR (r = 0.54, P < 0.05). Finally, the PR of apoC-III2 was strongly correlated with the proportion of LDL <255 A (r = 0.72, P = 0.002). These results suggest that all apoC-III isoforms, especially the predominant CIII1 and CIII2 isoforms, contribute to hypertriglyceridemia and that apoC-III2 may play a significant role in the expression of the small, dense LDL phenotype.

Tu-W25:7 Porphyromonas gingivalis increases the expression of APO M and cleaves APO B-100 in LDL in whole blood — effects on fibroblast proliferation

Tu-W25:7 Porphyromonas gingivalis increases the expression of APO M and cleaves APO B-100 in LDL in whole blood — effects on fibroblast proliferation

Effect of n-3 fatty acids on metabolism of apoB100-containing lipoprotein in type 2 diabetic subjects

The effect of long-chain n-3 PUFA on the metabolism of apoB100-containing lipoprotein in diabetic subjects is not fully understood. The objective of the present study was to determine the effect of a daily intake of 1080 mg EPA and 720 mg DHA for diabetic subjects on the kinetics of apoB100-containing lipoprotein in the fasting state. A kinetic study was undertaken to determine the mechanisms involved in the effects of n-3 fatty acids in terms of a decrease in triacylglycerol level in type 2 diabetic patients. We have studied the effect of fish oils on the metabolism of apoB100 endogenously labelled by [5,5,5-2H3]-leucine in type 2 diabetic patients in the fasting state. The kinetic parameters of apoB100 in VLDL, intermediate-density lipoprotein and LDL were determined by compartmental modelling in five diabetic subjects before and 8 weeks after n-3 fatty acid treatment. Treatment did not change the plasma cholesterol level (0.801 (sd 0.120) v. 0.793 (sd 0.163) mmol/l) but lowered the plasma triacylglycerol level (1.776 (sd 0.280) v.1.356 (sd 0.595) mmol/l; P < 0.05). Treated patients showed a decrease in VLDL apoB100 concentration (0.366 (sd 0.030) v.0.174 (sd 0.036) g/l; P < 0.05) related to a decrease in VLDL 1 production (1.49 (sd 0.23) v.0.44 (sd 0.19) mg/kg per h; P < 0.05) and an increase in the VLDL conversion rate (0.031 (sd 0.024) v.0.052 (sd 0.040) per h; P < 0.05), with no change in fractional catabolic rates. Treatment led to a higher direct production of intermediate-density lipoprotein (0.02 (sd 0.01) v.0.24 (sd 0.12) mg/kg per h; P < 0.05). In conclusion, the present study, conducted in the fasting state, showed that supplementation with n-3 fatty acids in type 2 diabetic patients induced beneficial changes in the metabolism of apoB100-containing lipoprotein.

Efficacy and tolerability of combined treatment with l-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus

Lipoprotein(a) [Lp(a)] concentration is generally related to coronary artery disease (CAD) and cerebrovascular disease. However, at present, few interventions are available to lower Lp(a) concentrations. We investigated the effects of l-carnitine, co-administered with simvastatin, on hyper-Lp(a) in patients with type 2 diabetes mellitus. We conducted an open, randomised, parallel-group study, in one investigational center (University hospital). Fifty-two patients with type 2 diabetes mellitus, a triglyceride serum levels <400 mg/dL (<4.5 mmol/L), and Lp(a) serum levels >20 mg/dL (0.71 mmol/L) were randomised to receive simvastatin alone ( n = 26) or simvastatin plus l-carnitine ( n = 26) for 60 days. Simvastatin was administered, in both groups, at a dosage of 20 mg/day, while l-carnitine was administered at a dosage of 2 g/day once daily. Both treatments were given orally. Serum levels of triglycerides, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol (total cholesterol minus HDL cholesterol), apolipoprotein B, and Lp(a) were measured at baseline and 60 days after starting treatment. No difference in time by groups (simvastatin and simvastatin plus l-carnitine) were observed in the reduction of LDL cholesterol, non-HDL cholesterol, and apoB serum levels. On the other hand, Lp(a) serum levels increase from baseline to 60 days in the simvastatin group alone versus a significant decrease in the combination group. Our findings provide support for a possible role of combined treatment with l-carnitine and simvastatin in lowering Lp(a) serum levels in patients with type 2 diabetes mellitus than with simvastatin alone. Our results strongly suggest that l-carnitine may have a role among lipid-lowering strategies.