apoC-III In VLDL Research Articles

The risk of cardiovascular events with increased apolipoprotein CIII: A systematic review and meta-analysis

Apolipoprotein CIII (apoC-III) is an atherogenic protein found on HDL, VLDL and LDL. The objective of this study is to review the literature on the association of blood apoC-III level with cardiovascular events and the dose-response relationship for this association. MEDLINE, EMBASE, BIOSIS, CINAHL, Clinicaltrials.gov, grey-literature sources, contact with investigators, and reference lists of studies, without language restrictions, were reviewed. Twelve studies (5 retrospective and 7 prospective) with a total of 3163 cases of cardiovascular events met inclusion criteria for this systematic review. The pooled standardized mean difference showed significantly higher levels of apoC-III in the non-HDL fraction of plasma (representing apoC-III in VLDL and LDL) in those with cardiovascular disease compared with controls; no difference for apoC-III levels in HDL; and, a trend toward higher total plasma apoC-III in the cases. Pooled risk estimates from the meta-analysis were 2.48 (1.48-4.32; non-HDL apoC-III), 1.09 (0.65-1.82; HDL apoC-III), and 1.33 (1.07-1.66; total apoC-III) for a cardiovascular event with a 5-mg/dL increase in apoC-III. The current body of literature includes several methodologically sound studies that together provide consistent evidence for an association of cardiovascular events with blood apoC-III level in total plasma or in VLDL and LDL. More data are needed to determine importance of levels of apoC-III in specific lipoproteins for cardiovascular risk assessment and management and to elucidate the interaction between triglycerides and apoC-III in relation to risk of cardiovascular disease.

Racial differences between African-American and white women in insulin resistance and visceral adiposity are associated with differences in apoCIII containing apoAI and apoB lipoproteins.

BackgroundAfrican-Americans have higher HDL, less visceral adipose tissue (VAT) and lower triglyceride (TG) and apoCIII concentrations than whites, despite being more insulin-resistant. We studied in African-American and white women the influences of insulin resistance and VAT on the apoAI concentrations of two HDL subspecies, one that contains apoCIII that is associated with increased risk of coronary heart disease (CHD) and one that does not have apoCIII that is associated with decreased CHD; and on the apoCIII concentrations of HDL and of the apoB lipoproteins.MethodsThe participants were 32 women (14 African-Americans, 18 white) of similar age (39 ± 12 vs. 42 ± 11y). Mean BMI was 34 kg/m2 in the African-Americans compared to 30 in the whites. A standard diet (33% fat, 52% carbohydrate, 15% protein) was provided for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model.ResultsAfter controlling for SI, African-Americans have a higher mean apoAI level in HDL with apoCIII compared with whites (12.9 ± 2.8 and 10.9 ± 2.9 mg/dL, respectively, P = 0.05). SI was associated with higher apoAI in HDL with apoCIII, whereas VAT was not associated with this HDL subspecies. This pattern of results was reversed for apoCIII concentrations in apoB lipoproteins. After adjusting for SI, African-Americans had lower apoCIII in apoB lipoproteins. SI was associated with lower apoCIII in total apoB lipoproteins, whereas VAT was associated with higher apoCIII in all the apoB lipoproteins. Additional adjustment for VAT tended to reduce the difference in apoCIII between the groups.ConclusionsAfrican-American women have a higher HDL with apoCIII level than whites when controlled for insulin sensitivity. African-Americans have lower insulin sensitivity. Insulin sensitivity is associated with higher levels of HDL with apoCIII. ApoCIII levels in VLDL are lower in African-American women than whites, also affected by insulin sensitivity which is associated with low apoCIII in VLDL. VAT has a strong association with apoCIII in apoB lipoproteins but not with apoAI in HDL with apoCIII.Trial registrationClinicalTrials.gov Identifier: NCT00484861

Abstract 411: Effect of Sitagliptin Therapy on Triglyceride-Rich Lipoprotein Kinetics in Patients With Type 2 Diabetes

Postprandial hyperlipemia is a key metabolic feature of insulin-resistant states and an important risk factor for cardiovascular disease, due to the accumulation of atherogenic triglyceride (TG)-rich lipoproteins (TRL) from both hepatic and intestinal origin. Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 that has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes (T2D) presumably through incretin hormone-mediated improvements in islet function. The objective of the present study was to investigate the effects of sitagliptin therapy on the kinetics of TRL apolipoprotein (apo) B-48, VLDL apoB-100, apoE and apoC-III in patients with type 2 diabetes. Twenty two subjects with T2D (18 men and 4 postmenopausal women, mean age of 58.2±3.8 y) were recruited in this double-blind crossover study using sitagliptin 100 mg/d or placebo for a 6-week period each, with a 4-week washout period between the two phases. At the end of each phase of treatment, the in vivo kinetics of the different apolipoproteins were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h with the participants in a constantly fed state. Sitagliptin therapy vs. placebo significantly reduced concentrations of fasting plasma TG (-15.4%, 0.03), apoB-48 (-16.3%, P=0.03), free fatty acids (-9.5%, P= 0.04), HbA1C (placebo: 7.0%±0.8 vs sitagliptin: 6.6%±0.7, P<0.0001), and plasma glucose (-13.5%, P=0.001) without any significant effect on insulin level. Treatment with sitagliptin significantly reduced the pool size of TRL apoB-48 by -20.8% (P=0.03), due to a reduction in the production rate of these particles (-16.0%, P=0.03). VLDL apoB-100 pool size was also significantly decreased by sitagliptin therapy (-9.3%, P=0.03), mainly due to a reduction in the hepatic secretion of these lipoproteins (-9.2%, P=0.06). Finally, sitagliptin treatment had no effect on VLDL apoC-III and apoE levels, but reduced both fractional catabolic and production rates of VLDL apoE (-10.6%, P=0.05 and -12.7%, P=0.04). In conclusion, treatment with sitagliptin for 6 weeks reduces TG-rich apoB-containing lipoproteins levels through a reduction in the synthesis of these particles in patients with T2D.

Apolipoprotein-defined lipoproteins and apolipoproteins: Associations with abnormal albuminuria in type 1 diabetes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort

AimsDyslipoproteinemia has been associated with nephropathy in diabetes, with stronger correlations in men than in women. We aimed to characterize and compare plasma lipoprotein profiles associated with normal and increased albuminuria in men and women using apolipoprotein-defined lipoprotein subclasses and simple apolipoprotein measures. MethodsThis is a cross-sectional study in a subset (154 women and 282 men) of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, using samples obtained in 1997–9. Immunochemical methods were used to quantify plasma apolipoprotein-based lipoprotein subclasses and individual apolipoprotein levels. ResultsIn adjusted analyses, elevated Lipoprotein-B (Lp-B) was significantly associated with macroalbuminuria in men [odds ratios (OR) and 95% confidence interval (CI): 2.13 (1.15–3.97)] and women [3.01 (1.11–8.12)], while association with Lp-B:C was observed only in men [1.84 (1.19–2.86)]. For individual apolipoproteins the following significant associations with macroalbuminuria were observed in men only: Apolipoprotein B (ApoB) [1.97 (1.20–3.25)], Apo-AII [0.52 (0.29–0.93)], ApoC-III [1.95 (1.16–3.30)], “ApoC-III in VLDL” (heparin–manganese precipitate) [1.88 (1.16–3.04)], and “ApoCIII in HDL” (heparin–manganese supernatant) [2.03 (1.27–3.26)], all P<0.05). ConclusionsAtherogenic apolipoprotein-based profiles are associated with nephropathy in Type 1 diabetic men and to a lesser extent in women. The difference could result from the greater prevalence and severity of dyslipoproteinemia, and from the greater prevalence of renal dysfunction, in men vs women.

Abstract P064: Weight Loss Induced by Healthy Diets Reduces Atherogenic Lipoproteins that Contain ApoC-III Independent of Dietary Macronutrient Content

Background: Weight-loss improves lipid risk factors for cardiovascular disease risk. However, the effect of weight loss on VLDL, LDL and HDL subtypes that contain apoC-III, newly emerging as important predictors of CVD, is not known. Further, the effects of dietary macronutrient composition on changes in apoC-III-containing lipoproteins in the presence of weight loss have not been studied. Methods: The Pounds Lost Trial randomized 811 overweight and obese subjects to four healthful diets that varied in emphasis of unsaturated fat, protein, and carbohydrate for 24 months. A random 50% subsample was selected for analysis of lipoprotein subfractions (~100 per study diet). Plasma samples were collected at baseline and after 24 months and stored at -80C to await analysis. Whole plasma was fractionated first by apoC-III content and then by density (VLDL, IDL+LDL, HDL) to produce 6 subfractions: VLDL with apoC-III, VLDL without apoC-III, IDL+LDL with apoC-III, IDL+LDL without apoC-III, HDL with apoC-III, HDL without apoC-III. Apolipoprotein and lipid concentrations were measured in these subfractions. The primary aim was to determine whether macronutrient content of diets for weight loss influenced changes after weight loss in concentrations and compositions of the 6 lipoprotein subfractions. A secondary analysis determined the relation between amount of weight-loss and change in the lipoproteins, adjusted for baseline BMI, age, race, and sex. Results: On average, the study population had lost 5% of their body weight at 2 years regardless of randomized diet group. Changes in lipoprotein subfractions from baseline to 2 years were similar among the 4 diet groups. Multiple regression analysis determined that degree of weight loss significantly predicted reductions in apoC-III in VLDL, LDL and HDL. For example, a 5% weight loss corresponded to reductions in apoC-III in VLDL of 14% (95% CI: 8.0%, 19.8%), LDL of 5.5% (0.3%, 8.6%), and HDL of 2.2% (0.1%, 4.4%). Weight loss notably predicted a decrease in the apoB concentration of LDL with apoC-III. The concentration of LDL with apoC-III was the strongest predictor of CVD in several cohorts. In contrast, weight loss predicted increases in apoE in VLDL and LDL. ApoE increases the clearance from plasma of VLDL and LDL and reduces the formation of LDL from VLDL. Conclusion: Weight loss achieved through healthful diets reduces apoC-III and atherogenic LDL with apoC-III but increases apoE in apoB-lipoproteins regardless of macronutrient emphasis. These effects on lipoprotein subfractions represent a novel mechanism by which weight loss may reduce cardiovascular disease risk.

Dual PPAR α / γ Agonism Normalizes Lipoprotein Profile of Renal Dyslipidemia.

Chronic kidney disease (CKD) is characterised by specific lipoprotein abnormalities and insulin resistance. Dual activation of the peroxisome proliferators-activated receptors (PPAR) α and γ can significantly improve insulin sensitivity. The aim of the study was to investigate the effects of a dual PPAR α/γ agonist on lipoprotein abnormalities in patients with CKD. One mg of the dual PPAR α/γ agonist tesaglitazar was given once daily during six weeks to CKD patients, and to healthy subjects. Plasma lipids, apolipoproteins (apo) and discrete lipoprotein subclasses were measured at baseline and end of treatment. In the CKD patients apoA-I increased significantly by 9%, and apoB decreased by 18%. There was an increase of apoC-III in HDL by 30%, and a parallel decrease of apoC-III in VLDL + LDL by 13%. Both the apoB-containing cholesterol-rich and the triglyceride-rich subclasses decreased significantly. With the exception of ApoC-III,all plasma lipids apolipoproteins and lipoprotein subclasses were reduced by treatment down to similar levels as the baseline levels of a healthy group of reference subjects. This study suggests that by improving insulin sensitivity a dual PPAR α/γ agonist has the potential to normalise most of the lipoprotein abnormalities in patients with CKD.

Abstract 322: Effect of Atorvastatin on Very-Low-Density Lipoprotein Triglyceride Kinetics in Obese Men

Background Hypertriglyceridemia is a risk factor for cardiovascular disease. Atorvastatin effectively decreases plasma and VLDL triglyceride concentrations in humans, but the mechanism of action is unknown. This study examined the effect of atorvastatin on VLDL triglyceride (VLDL-TG) metabolism in obese men. Hypothesis: Atorvastatin decreases VLDL-TG concentrations by increasing VLDL-TG catabolism. Methods: 25 obese men (mean ± SEM: age 52 ± 3 years, BMI 34.5 ± 1.4 kg/m 2 , plasma triglyceride 1.9 ± 0.1 mmol/L, HDL cholesterol 1.00 ± 0.05 mmol/L) were studied in a two-arm parallel group study design. Eligible subjects entered a 3 week run-in dietary stabilizing period at the end of which they were randomized to a 6 week treatment period of either atorvastatin 40 mg/day (ATV) or placebo. VLDL-TG kinetics were examined using stable isotope methods and compartmental modelling. Results: ATV decreased plasma TG, VLDL apoB and VLDL apoC-III concentrations compared with placebo (p&lt;0.05). Compared with placebo, ATV decreased VLDL-TG concentration ( ATV vs. placebo) (-40% vs. +2%, p&lt;0.01) and increased VLDL-TG fractional catabolic rate (FCR; +54 % vs. -7%, p&lt;0.01). ATV did not alter VLDL-TG production rate. Change in VLDL-TG concentration was positively correlated with change in VLDL apoB (r = 0.81, p&lt;0.01) and VLDL apoC-III (r = 0.65, p=0.02) concentrations, and negatively correlated with VLDL-TG FCR (r = -0.54, p=0.05). Change in VLDL-TG FCR was negatively correlated with VLDL apoC-III, but this failed to reach statistical significance (r = -0.53, p=0.06). Conclusions: In obese men, ATV decreased plasma and VLDL-TG concentrations chiefly by increasing VLDL-TG catabolism, with no appreciable effect on VLDL-TG synthesis. Our data suggest that reduction in apoC-III concentration with ATV may explain, in part, the increase in VLDL-TG catabolism.

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H₃]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.

Presence of Apolipoprotein C‐III Attenuates Apolipoprotein E‐Mediated Cellular Uptake of Cholesterol‐Containing Lipid Particles by HepG2 Cells

Apolipoprotein C-III (apoC-III) decreases the apolipoprotein E (apoE)-mediated uptake of lipoprotein remnants by the liver, and a high plasma concentration of apoC-III in VLDL is associated with hypertriglyceridemia and the risk of coronary heart disease. In this study, we prepared lipid emulsions containing triolein, phosphatidylcholine and cholesterol as model particles of lipoproteins, and examined the roles of apoC-III in apoE-mediated uptake of emulsions by HepG2 cells. Cholesterol in emulsion particles enhanced the apoE-mediated uptake via heparan sulfate proteoglycan and LDL receptor-related protein pathways. The amount of apoE bound to emulsion particles was increased by the presence of cholesterol at the particle surface, whereas cholesterol had no effect on the binding amount of apoC-III. Surface cholesterol alleviated the inhibitory effect of apoC-III on apoE incorporation into the emulsion surface. However, ApoC-III almost completely inhibited the apoE-mediated uptake of cholesterol-containing emulsions despite sufficient binding of apoE to emulsions. These findings suggest that apoC-III attenuates the binding of apoE to the lipoprotein surface and apoE-mediated cellular uptake of lipoprotein remnants. Furthermore, cholesterol may affect these functions of apoC-III and apoE involved in the clearance of lipoprotein remnants.

Dietary interventions that lower lipoproteins containing apolipoprotein C-III are more effective in whites than in blacks: results of the OmniHeart trial

Blacks have lower average triglyceride and LDL cholesterol concentrations than do whites but higher rates of coronary heart disease. Apolipoprotein (apo) C-III in VLDL and LDL stimulates atherogenic processes in vascular cells. In blacks, the concentration of lipoproteins with apo C-III is unknown, and the response to dietary strategies that lower triglyceride and apo C-III has not been investigated We compared the concentration of and dietary effects on apo C-III-containing lipoproteins in blacks and whites. In a randomized, 3-period feeding study [OmniHeart (Optimal Macronutrient Intake Trial to Prevent Heart Disease)], we measured lipoprotein concentrations in 89 blacks and 73 whites who consumed self-selected diets (baseline) and after 3 healthful diets emphasizing carbohydrate, unsaturated fat, or protein. Participants had prehypertension or hypertension, and 79% were overweight or obese. While consuming self-selected diets, blacks had lower apo C-III in total plasma, VLDL, and LDL than did whites. Unsaturated fat and protein diets lowered plasma apo C-III (16% and 18%, respectively) and triglyceride (12% and 21%, respectively) in whites but not in blacks, reducing racial differences. Most important, blacks had a lower concentration of atherogenic LDL with apo C-III at baseline and after study diets (34-41% lower, P < 0.02). The molar ratio of apo E to apo B was higher in blacks than in whites in total plasma and LDL at baseline and after the study diets. Blacks have lower concentrations of atherogenic lipoproteins that contain apo C-III than do whites when consuming diverse diets and an attenuated dietary response of triglyceride and apo C-III. Dietary efforts to lower triglyceride and apo C-III may be more effective in whites than in blacks. The OmniHeart Trial was registered at www.clinicaltrials.gov as NCT00051350.

Effects of atorvastatin and n−3 fatty acid supplementation on VLDL apolipoprotein C-III kinetics in men with abdominal obesity

Disturbed apolipoprotein (apo) C-III metabolism in obese subjects may account for hypertriglyceridemia and increased risk of cardiovascular disease. Atorvastatin and fish oils decrease plasma triglycerides and VLDL concentrations, but the underlying mechanisms are not fully understood. We studied the independent and combined effects of atorvastatin and fish oils on the metabolism of VLDL apo C-III in obese men. We carried out a 6-wk randomized, placebo-controlled, 2 x 2 factorial intervention study of atorvastatin (40 mg/d) and fish oils (4 g/d) on VLDL apo C-III kinetics in the postabsorptive state in 39 abdominally obese men using intravenous administration of d(3)-leucine. VLDL apo C-III isotopic enrichments were measured by using gas chromatography-mass spectrometry with kinetic parameters derived by using a multicompartmental model. Atorvastatin significantly (P < 0.05, main effect) increased the VLDL apo C-III fractional catabolic rate (+0.06 +/- 0.003 pools/d) without significantly altering its production rate (-0.14 +/- 0.18 mg . kg(-1) . d(-1)), accounting for a significant reduction in plasma VLDL apo C-III pool size (-44 +/- 17 mg/L). Fish-oil supplementation significantly decreased plasma triglycerides but did not significantly alter plasma VLDL apo C-III concentrations or kinetic parameters. Combination treatment provided no additional effect on VLDL apo C-III concentrations or kinetics compared with atorvastatin alone. In obesity, the triglyceride-lowering effect of atorvastatin, but not fish oils, is associated with increased VLDL apo C-III fractional catabolism and hence lower VLDL apo C-III concentrations. Combination treatment provided no significant additional improvement in VLDL apo C-III metabolism compared with atorvastatin alone.

Dose-Dependent Effect of Rosuvastatin on VLDL–Apolipoprotein C-III Kinetics in the Metabolic Syndrome

OBJECTIVE—Dysregulated apolipoprotein (apo)C-III metabolism may account for hypertriglyceridemia and increased cardiovascular risk in the metabolic syndrome. This study investigated the dose-dependent effect of rosuvastatin on VLDL apoC-III transport in men with the metabolic syndrome.RESEARCH DESIGN AND METHODS—Twelve men with the metabolic syndrome were studied in a randomized double-blind crossover trial of 5-week intervention periods with placebo, 10 mg rosuvastatin, or 40 mg rosuvastatin, with 2-week placebo washouts between each period. VLDL apoC-III kinetics were examined using a stable isotope method and compartmental modeling at the end of each intervention period.RESULTS—Compared with placebo, there was a significant dose-dependent reduction with rosuvastatin in plasma triglyceride and VLDL apoC-III concentrations. Rosuvastatin significantly (P < 0.05) increased VLDL apoC-III fractional catabolic rate (FCR) and decreased its production rate, with a significant (P < 0.05) dose-related effect. With 40 mg rosuvastatin, changes in VLDL apoC-III concentration were inversely associated with changes in VLDL apoC-III FCR and positively associated with VLDL apoC-III production rate (P < 0.05). Changes in VLDL apoC-III concentration and production rate were positively correlated with changes in VLDL apoB concentration and production rate and inversely correlated with VLDL apoB FCR (P < 0.05). Similar associations were observed with 10 mg rosuvastatin but were either less or not statistically significant.CONCLUSIONS—In this study, rosuvastatin decreased the production and increased the catabolism of VLDL apoC-III, a mechanism that accounted for the significant reduction in VLDL apoC-III and triglyceride concentrations. This has implications for the management of cardiometabolic risk in obese subjects with the metabolic syndrome.

Use of Intralipid for kinetic analysis of HDL apoC-III: evidence for a homogeneous kinetic pool of apoC-III in plasma

Apolipoprotein C-III (apoC-III) is an important regulator of lipoprotein metabolism. Radioisotope and stable isotope kinetic studies show differing results in relation to the kinetics of apoC-III in HDL. Kinetic analysis of HDL apoC-III may be difficult because of its low concentration, as well as the presence of other apoproteins at higher concentration, in the HDL fraction. We used Intralipid(R) (IL), known to preferentially extract apoC proteins from plasma, as a means of extracting apoC-III from HDL before apoprotein separation by isoelectric focusing gel electrophoresis for the measurement of tracer enrichment. Protein purity was assessed by an isoleucine-to-leucine (Ile/Leu) ratio, as apoC-III contains no isoleucine. We compared apoC-III kinetics in 14 men using a bolus infusion of deuterated leucine. The Ile/Leu ratio for IL-extracted HDL (IL-HDL) apoC-III (3.0 +/- 0.7%) was not different from that of VLDL apoC-III (2.6 +/- 0.6%) but was significantly lower than that of untreated HDL apoC-III (9.0 +/- 2.9%) (P < 0.001). The isotopic enrichment curves and fractional catabolic rates (FCRs) for IL-HDL apoC-III were not different from those of VLDL apoC-III. In contrast, HDL apoC-III had significantly lower isotopic enrichments and FCRs than IL-HDL apoC-III (P < 0.001). In conclusion, this simple IL method can be used to isolate apoC-III from HDL with minimal interference from other HDL apoproteins, and it demonstrates that the kinetics of apoC-III in VLDL and HDL are similar, supporting the concept of a single kinetically homogeneous pool of apoC-III in plasma.

Effect of the Combination of Methyltestosterone and Esterified Estrogens Compared With Esterified Estrogens Alone on Apolipoprotein CIII and Other High-Density Lipoproteins in Surgically Postmenopausal Women

High plasma triglycerides are an independent risk factor for coronary heart disease (CHD), and levels are reduced by androgens. Methyltestosterone, when combined with esterified estrogens, reportedly relieves vasomotor symptoms in postmenopausal women and also improves sexual function and quality of life. Triglycerides are carried in plasma on very-low-density (VLDL) and low-density (LDL) lipoprotein. Apolipoprotein CIII (apoCIII), a strong risk factor for CHD, impairs the metabolism of both VLDL and LDL, thereby contributing to elevated triglycerides. This study evaluated a daily oral 2.5-mg dose of methyltestosterone, added to 1.25 mg esterified estrogens daily, on levels of lipoproteins and apolipoproteins, particularly those containing apoCIII. This regimen was compared with esterified estrogens alone, in the same dose, in a 10-week trial following a randomized, double-blind design. Forty surgically postmenopausal women assigned to combination treatment were compared with 39 others given esterified estrogen alone. The groups were similar in age, body mass index, and follicle-stimulating hormone levels at the outset. Women on combined treatment had significant increases in both free and bioavailable testosterone, estradiol, and weakly bound estradiol at 8 weeks and significant decreases in estrone, total estradiol, and sex hormone-binding globulin (SHBG). With combination treatment, changes in weakly bound estradiol correlated inversely with changes in total apoCIII, HDL-apoCIII, and LDL-apoCIII. Changes in estrone and SHBG were positively related to triglyceride levels, and changes in SHBG also correlated with LDL-apoCIII. None of the lipoprotein changes correlated significantly with changes in serum testosterone. Compared with esterified estrogen alone, combination treatment lowered plasma total triglycerides by 11%, total cholesterol by 10%, and HDL cholesterol by 24%. Other effects were significant decreases in apoCI by 13%, in apoCII by 14%, in apoCIII by 14%, and in apolipoprotein E by 13%. Levels of apolipoprotein B did not change significantly. In the combined treatment group, apoCIII decreased significantly by 62%, 35%, and 17% in VLDL, LDL, and HDL, respectively, compared with treatment with esterified estrogen only (Fig. 1). Methyltestosterone plus esterified estrogen did not alter levels of VLDL or LDL that lacked apoCIII. There were no between-group differences in adverse effects such as headache, acne, and breast pain.Fig. 1: ApoCIII concentrations in lipoprotein subfractions: effect of the combination of methyltestosterone and esterified estrogens compared with that of esterified estrogens alone. The mean change from baseline is shown. P values are computed by unpaired t tests of the differences in the 2 groups. ApoCIII concentrations were measured in the VLDL and LDL apoCIII+ particles, ie, those that were retained by anti-apoCIII immunoaffinity chromatography. ApoCIII was measured in the total HDL. Reproduced with permission. J Clin Endocrinol Metab 2004;89:2207–2213. Copyright 2004, Endocrine Society. All rights reserved.It appears that adding methyltestosterone to esterified estrogen in postmenopausal women has favorable effects on lipoprotein-related risk factors, in particular apoCIII concentrations in VLDL and LDL—a predictor of CHD. Methyltestosterone may lower plasma triglycerides through a reduction in apoCIII.

Increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia

Apolipoprotein (apo) C-III plays an important role in regulating plasma triglyceride (TG) metabolism. In order to further investigate the plasma metabolism of apoC-III in hypertriglyceridemic subjects, we have studied the plasma kinetics of VLDL apoC-III, HDL apoC-III and total plasma apoC-III with a primed constant intravenous infusion of deuterated leucine in a group of male patients with mixed hyperlipidemia (type IIb hyperlipoproteinemia, HLP, n = 6) and in a group with type III HLP ( n = 6). Compared to normolipidemic control subjects ( n = 5), patients with type IIb and type III HLP had significantly higher levels of plasma TG (0.89 ± 0.15 mmol/l vs 2.56 ± 0.40 mmol/l vs 8.76 ± 1.39 mmol/l, respectively, P < 0.01), plasma apoC-III (9.5 ± 0.8 mg/dl vs 20.8 ± 2.5 mg/dl vs 41.7 ± 5.6 mg/dl, P < 0.01) and VLDL apoC-III (3.6 ± 0.8 mg/dl vs 14.6 ± 2.2 mg/dl vs 35.4 ± 5.1 mg/dl, P < 0.01). VLDL apoC-III production rates were significantly elevated in type IIb and type III patients (1.35 ± 0.23 mg kg −1 day −1 vs 3.53 ± 0.43 mg kg −1 day −1 vs 5.60 ± 0.78 mg kg −1 day −1, P < 0.01), as were total plasma apoC-III production rates (1.80 ± 0.22 mg kg −1 day −1 vs 4.16 ± 0.44 mg kg −1 day −1 vs 7.26 ± 0.74 mg kg −1 day −1, P < 0.01). VLDL apoC-III but not total plasma apoC-III fractional catabolic rates were reduced in type IIb and type III patients. Together with our previous results showing an increase of apoC-III production in patients with type IV HLP, and in overweight subjects with reduced insulin sensitivity, our data suggest that increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia.

W09.200 Insulin resistance is associated with increased VLDL triglyceride and VLDL apoC-III production

W09.200 Insulin resistance is associated with increased VLDL triglyceride and VLDL apoC-III production

W09.200 Insulin resistance is associated with increased VLDL triglyceride and VLDL apoC-III production

W09.200 Insulin resistance is associated with increased VLDL triglyceride and VLDL apoC-III production

Indices related to apo CII and CIII serum concentrations and coronary heart disease: a case–control study

Background Triglycerides (TG) are carried in the circulation by diverse lipoprotein particles, which vary in their lipid and protein content, metabolism, and atherogenicity. Several indices related to apolipoproteins (apo) CII and CIII blood concentration have been proposed to reflect TG metabolism more accurately than the blood level of TG. In the present study we compared the distribution of those indices in coronary heart disease (CHD) patients and controls. Methods Ninety consecutively discharged patients with CHD and 209 healthy controls were included in the analysis. Demographic, clinical, and laboratory characteristics were obtained. Results The CHD patients differed appreciably from controls in several TG-related variables. After adjusting for cardiovascular risk factors, significant associations were found between CHD and the following: TG, VLDL-C, apo CIII, apo CIII in HDL, apo CIII in VLDL + LDL, apo CII- to- TG ratio, and apo CIII ratio (CIII in HDL/CIII in VLDL + LDL). Further adjustment for HDL-C substantially attenuated the above associations, except for those regarding apo CIII in VLDL + LDL (odds ratio (OR): 1.69 per 1 SD increment, 95%CI: 1.03–2.77) and apo CIII ratio (OR: 0.40 per 1 SD increment, 95%CI: 0.15–1.00). Conclusion Our results add to the growing evidence which links apo CIII concentration in VLDL + LDL to CHD. Further confirmation in prospective studies would be required before considering this measurement as a screening tool.

Alterations in Lipoprotein Composition in Peritoneal Dialysis Patients

Dyslipidemia is common among patients with end-stage renal disease, whether treated by hemodialysis (HD) or peritoneal dialysis (PD). To better understand the specific lipoprotein abnormalities in PD patients, we measured the lipid and apolipoprotein (Apo) composition of the four major classes of plasma lipoproteins in PD patients, HD patients, and healthy control subjects: very low density (VLDL), intermediate density (IDL), low density (LDL), and high density lipoproteins (HDL). Fasting plasma samples were obtained from 15 nondiabetic PD patients, 15 nondiabetic HD patients, and 16 healthy control subjects, all from a cross section of patients and subjects in the region of Göteborg, Sweden. Lipoproteins were isolated by preparative ultracentrifugation, and lipid and apolipoprotein concentrations were measured by gas chromatography and electroimmunoassay, respectively. Alterations in lipoprotein composition were apparent in all four lipoprotein density classes from PD and HD patients. VLDL contained a significantly higher concentration of ApoCIII in both HD and PD patients, and an elevation of free cholesterol, triglyceride, ApoB, ApoCII, and ApoE in PD patients. IDL from both PD and HD patients contained an excess of free and esterified cholesterol and triglyceride and significantly elevated levels of ApoB, ApoCII, ApoCIII, and ApoE. LDL had a higher concentration of ApoB in PD patients and elevated triglyceride and ApoCIII in both PD and HD patients. HDL isolated from PD patients had lower free cholesterol and ApoAI levels compared to control subjects, but these were not significantly different from HD patients. An increase in lipid and apolipoprotein mass in IDL, and an enrichment of ApoCIII in VLDL, IDL, and LDL were observed in both HD and PD patients. The predominant alteration in lipoprotein composition distinguishing PD patients from HD patients was an elevation of ApoB in LDL. Further study of these alterations in lipoprotein composition in PD patients will be helpful in understanding the underlying causes of dyslipidemia and, ultimately, to the selection of hypolipidemic drugs or other treatments to reduce the cardiovascular risks associated with dyslipidemia in these patients.

Abnormal lipid and apolipoprotein composition of major lipoprotein density classes in patients with chronic renal failure

To characterize the abnormalities of lipoprotein composition in patients with chronic renal failure (CRF), the lipid and apolipoprotein (apo) concentrations and compositions of major lipoprotein density classes were determined in 20 subjects with moderate to advanced renal failure (GFR 5-59 ml/min) and nine controls. Patients were divided in 14 normotriglyceridaemic (NTG) subjects with triglyceride (TG) levels < or = 1.7 mmol/l (150 mg/dl) and six hypertriglyceridaemic (HTG) subjects with TG > or = 1.7 mmol/l. Lipoproteins were isolated by preparative ultracentrifugation: very low density (VLDL), intermediate density (IDL), low density (LDL) and high density (HDL) lipoproteins. Although all density classes were characterized by abnormal concentration and composition of some lipid and apo constituents, the most profound changes occurred in IDL and HDL. Cholesterol levels were elevated in VLDL and IDL with little change in LDL and reduced in HDL. TG levels were increased in all density classes. ApoB levels were increased in VLDL, IDL and LDL of all CRF patients reaching the significance levels in VLDL and IDL of HTG (P < 0.01). In IDL, the levels of apoC-peptides and apoE were increased (P < 0.01). ApoC-peptides and apo E were also elevated in VLDL of NTG and HTG, but their increase was only significant in HTG (P < 0.01). In LDL, the concentration of apoC-II and apoC-III was significantly increased (P < 0.05). However, in HDL there was significant (P < 0.01) reduction of apoA-I, apoA-II and apoC-peptides in both patient groups. The major compositional change was a significant increase in the relative contents of apoC-II and apoC-III in VLDL, IDL and LDL (P < 0.01). Results indicate that the characteristic feature of dyslipoproteinemia in CRF is the accumulation of partially delipidized TG-rich apoB-containing lipoproteins enriched in apoC-peptides and distributed characteristically in the IDL density-range irrespective of fasting TG concentrations. Increased levels of these ¿remnant lipoproteins' and reduced levels of HDL may represent risk factors for atherogenesis and progressive renal disease.