apoB Fractional Catabolic Rate Research Articles

Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases low-density lipoprotein apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial

BackgroundThe substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown. ObjectivesThis study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia. MethodsMales and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins. ResultsSubstituting MUFAs for SFAs had no impact on triglyceride-rich lipoprotein apoB-48 fractional catabolic rate (FCR) (Δ = –8.9%, P = 0.4) and production rate (Δ = 0.0%, P = 0.9), although it decreased very low-density lipoprotein apoB-100 pool size (PS) (Δ = −22.5%; P = 0.01). This substitution also reduced low-density lipoprotein cholesterol (LDL-C) (Δ = −7.0%; P = 0.01), non–high-density lipoprotein cholesterol (Δ = −2.5%; P = 0.04), and LDL apoB-100 PS (Δ = −6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet. ConclusionsThis study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia. Trial registrationThis trial was registered as clinicaltrials.gov as NCT03872349.

ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia—Brief Report

The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5-2H3)-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04722068.

High-Dose DHA Has More Profound Effects on LDL-Related Features Than High-Dose EPA: The ComparED Study.

Supplementation with high-dose docosahexaenoic acid (DHA) increases serum low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations more than high-dose eicosapentaenoic acid (EPA). The mechanisms underlying this difference are unknown. To examine the phenotypic change in LDL and mechanisms responsible for the differential LDL-C response to EPA and DHA supplementation in men and women at risk of cardiovascular disease. In a double-blind, controlled, crossover study, 48 men and 106 women with abdominal obesity and subclinical inflammation were randomized to a sequence of three treatment phases: phase 1, 2.7 g/d of EPA; phase 2, 2.7 g/d of DHA; and phase 3, 3 g/d of corn oil. All supplements were provided as three 1-g capsules for a total of 3 g/d. The 10-week treatment phases were separated by a 9-week washout period. In vivo kinetics of apolipoprotein (apo)B100-containing lipoproteins were assessed using primed-constant infusion of deuterated leucine at the end of each treatment in a subset of participants (n = 19). Compared with EPA, DHA increased LDL-C concentrations (+3.3%; P = 0.038) and mean LDL particle size (+0.7 Å; P < 0.001) and reduced the proportion of small LDL (-3.2%; P < 0.01). Both EPA and DHA decreased proprotein convertase subtilisin/kexin type 9 concentrations similarly (-18.2% vs -25.0%; P < 0.0001 vs control). Compared with EPA, DHA supplementation increased both the LDL apoB100 fractional catabolic rate (+11.4%; P = 0.008) and the production rate (+9.4%; P = 0.03). The results of the present study have shown that supplementation with high-dose DHA increases LDL turnover and contributes to larger LDL particles compared with EPA.

Differential Effects of Estrogen and Progestin on Apolipoprotein B100 and B48 Kinetics in Postmenopausal Women.

The distinct effects of the estrogen and progestin components of hormonal therapy on the metabolism of apolipoprotein (apo) B-containing lipoproteins have not been studied. We enrolled eight healthy postmenopausal women in a placebo-controlled, randomized, double-blind crossover study. Each subject received placebo, conjugated equine estrogen (CEE, 0.625 mg/day) and CEE plus medroxyprogesterone acetate (MPA, 2.5 mg/day) for 8 weeks in a randomized order, with a 4-week washout between phases. Main outcomes were the fractional catabolic rate (FCR) and production rate (PR) of apo B100 in triglyceride-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low -density lipoprotein (LDL) and of apo B48 in TRL. Compared to placebo, CEE increased TRL apo B100 PR (p = 0.04). CEE also increased LDL apo B100 FCR (p = 0.02), but this effect was offset by a significant increase in LDL apo B100 PR (p = 0.04). Adding MPA to CEE negated the CEE effects resulting in no significant changes in TRL apo B100 PR and LDL apo B100 FCR and PR relative to placebo. Relative to placebo, during CEE there was a trend toward a reduction in plasma apo B48 concentrations and PR (p = 0.07 and p = 0.12, respectively). Compared with CEE, CEE + MPA significantly increased TRL apo B48 FCR (p = 0.02) as well as apo B48 PR (p = 0.01), resulting in no significant changes in apo B48 concentration. Estrogen and progestin have independent and opposing effects on the metabolism of the atherogenic apo B100- and apo B48-containing lipoproteins.

Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance But Not VLDL Production in NAFLD.

Randomized controlled trials in nonalcoholic fatty liver disease (NAFLD) have shown that regular exercise, even without calorie restriction, reduces liver steatosis. A previous study has shown that 16 weeks of supervised exercise training in NAFLD did not affect total very low-density lipoprotein (VLDL) kinetics. The objective of the study was to determine the effect of exercise training on intrahepatocellular fat (IHCL) and the kinetics of large triglyceride (TG)-rich VLDL1 and smaller denser VLDL2, which has a lower TG content. This was a 16-week randomized controlled trial. A total of 27 sedentary patients with NAFLD participated in the trial. The intervention was composed of supervised exercise with moderate-intensity aerobic exercise or conventional lifestyle advice (control). VLDL1 and VLDL2-TG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes before and after the intervention. In the exercise group, maximal oxygen uptake increased by 31% ± 6% (mean ± SEM) and IHCL decreased from 19.6% (14.8%, 30.0%) to 8.9% (5.4%, 17.3%) (median [interquartile range]) with no significant change in maximal oxygen uptake or IHCL in the control group (change between groups, P < .001 and P = .02, respectively). Exercise training increased VLDL1-TG and apoB fractional catabolic rates, a measure of clearance, (change between groups, P = .02 and P = .01, respectively), and VLDL1-apoB production rate (change between groups, P = .006), with no change in VLDL1-TG production rate. Plasma TG did not change in either group. An increased clearance of VLDL1 may contribute to the significant decrease in liver fat after 16 weeks of exercise in NAFLD. A longer duration or higher-intensity exercise interventions may be needed to lower the plasma TG and VLDL production rate.

Abstract 125: Small Dense LDL ApoB Is Catabolized More Slowly Than Large LDL ApoB in Subjects With Combined Hyperlipidemia, and Rosuvastatin Enhances Its Clearance

LDL consists of particles varying in size, density, and composition. Small dense LDL (sdLDL) cholesterol (C) has been shown to be a better predictor of coronary heart disease risk than total LDL-C. Intensive statin therapy significantly lowers sdLDL-C as well as large buoyant LDL (lbLDL)-C. We tested the hypotheses that lbLDL and sdLDL apoB100 have different catabolic rates, and that statin therapy enhances the fractional catabolism of apoB100 in both particles. Six subjects (3 men and 3 women; age 63±5 years [mean±SEM]; BMI 25.5±1.5 kg/m 2 ) with combined hyperlipidemia (triglycerides [TG] 191±50 mg/dl; LDL-C 160±16 mg/dl; HDL-C 43±6 mg/dl) received placebo and rosuvastatin 40 mg/day for 8 weeks each in sequential order. At the end of each phase, the kinetics of apoB100 in triglyceride rich lipoproteins ([TRL] d &lt;1.019 g/ml), lbLDL ( d =1.019-1.044 g/ml), and sdLDL ( d =1.044-1.063 g/ml) were determined using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Compared to placebo, rosuvastatin markedly decreased the plasma levels of LDL-C (52%; P =0.0002), TG (32%; P =0.06), and total apoB (42%; P &lt;0.0001). ApoB100 pool size in TRL, lbLDL, and sdLDL decreased 32±6%, 39±5%, 41±4%, respectively. These changes were attributable to significant ( P &lt;0.05) increases in apoB100 fractional catabolic rates in TRL (45±16%), lbLDL (131±66%), and sdLDL (97±32%). During both the placebo and rosuvastatin phases, sdLDL apoB100 was catabolized more slowly than lbLDL apoB100 ( P =0.01 and 0.004, respectively). Rosuvastatin did not alter apoB100 production rate or the percent of TRL apoB100 converted to each LDL subfraction. Proteomic analysis of the LDL particles indicated that rosuvastatin increased apoD abundance in lbLDL and decreased apoAIV abundance in sdLDL. No significant effects on other apolipoproteins were noted. These data indicate that sdLDL apoB100 is catabolized significantly more slowly than lbLDL apoB100 in dyslipidemic subjects on placebo or statin therapy. Maximal dose rosuvastatin decreases plasma apoB concentrations by enhancing apoB100 catabolism in TRL, lbLDL, and sdLDL and alters the distribution of minor apolipoproteins in LDL subfractions.

Association of Plasma Ceramides and Sphingomyelin With VLDL apoB-100 Fractional Catabolic Rate Before and After Rosuvastatin Treatment.

The objective of the study was to examine post hoc associations between plasma sphingolipids and lipoprotein kinetics in men with the metabolic syndrome after rosuvastatin treatment. Plasma sphingolipid profiling, determined by tandem mass spectrometry, was performed in a randomized, double-blind, triple-crossover trial (n = 12) of 5-week treatment periods with placebo or rosuvastatin (10 or 40 mg/d) with 2-week washouts between treatments. Baseline plasma ceramides were associated with very low-density lipoprotein (VLDL) apolipoprotein (apo)-B-100 concentration (r = 0.58, P < .05) and inversely with VLDL apoB-100 fractional catabolic rate (FCR; r = -0.67, P = .02). Posttreatment changes with rosuvastatin (40 mg/d) in plasma ceramides were inversely associated with VLDL apoB-100 FCR (r = -0.62, P = .03) independent of changes in plasma triglycerides, cholesterol, and low-density lipoprotein-cholesterol. By contrast, baseline and postrosuvastatin treatment plasma sphingomyelin levels were not associated with apoB-100 kinetics. Plasma ceramides and sphingomyelin were not associated with the kinetics or concentrations of high-density lipoprotein apoA-I, and low-density lipoprotein apoB. In the metabolic syndrome, the ability of rosuvastatin to increase VLDL apoB-100 FCR may reflect ceramide-specific mechanistic actions and/or sphingolipid exchange.

Abstract 587: Dynamics of the Apolipoproteome: Turnover of HDL- and LDL-Associated Apolipoproteins by LC/MS/MS

The production rate and fractional catabolic rate of apoB and apoAI have been measured using stable isotope infusions of 13C or 2H leucine for many years and has led to our improved understanding of the pathophysiology of dyslipidemia and atherosclerosis. Modern tandem mass spectrometry methods have demonstrated the highly complex complement of proteins that associate with HDL and LDL and alterations in these proteins may impact lipoprotein function and cardiovascular risk. Very little is known about the turnover of the proteins that comprise the apolipoproteome. To study the fesability of measuring the turnover of multiple apolipoproteins associated with HDL and LDL we performed 20 hour IV infusions of U-13C labeled leucine in 20 healthy subjects. VLDL, LDL and HDL were isolated by ultracentrifugation and digested with trypsin. We analyzed peptides containing one leucine with analysis of multiple transitions using an Agilent triple quad. The enrichment of HDL and LDL peptides from multiple apolipoproteins were determined. The fractional synthesis of each protein was calculated by comparison of the average peptide enrichment for each protein to the average enrichment in VLDL apoB after 20 hours, at which time the VLDL apoB is fully turned over and its enrichment reflects the hepatic leucine precursor pool enrichment. Mean and SD values for HDL associated proteins are presented in table 1. The range of protein turnover rates on HDL confirms the dynamic state of the particle components. Fractional synthesis was similar for the majority of proteins on HDL and LDL with the notable exception of apoL1 and apoM. Using these methods, the regulation of the apolipoprotein composition of HDL and LDL can now be investigated.

Adding MUFA to a dietary portfolio of cholesterol-lowering foods reduces apoAI fractional catabolic rate in subjects with dyslipidaemia

The present randomised parallel study assessed the impact of adding MUFA to a dietary portfolio of cholesterol-lowering foods on the intravascular kinetics of apoAI- and apoB-containing lipoproteins in subjects with dyslipidaemia. A sample of sixteen men and postmenopausal women consumed a run-in stabilisation diet for 4 weeks. Subjects were then randomly assigned to an experimental dietary portfolio either high or low in MUFA for another 4 weeks. MUFA substituted 13·0% of total energy from carbohydrate (CHO) in the high-MUFA dietary portfolio. Lipoprotein kinetics were assessed after the run-in and portfolio diets using a primed, constant infusion of [2H3]leucine and multicompartmental modelling. The high-MUFA dietary portfolio resulted in higher apoAI pool size (PS) compared with the low-MUFA dietary portfolio (15·9% between-diet difference, P¼0·03). This difference appeared to be mainly attributable to a reduction in apoAI fractional catabolic rate (FCR) after the high-MUFA diet (25·6%, P¼0·02 v. pre-diet values), with no significant change in production rate. The high-MUFA dietary portfolio tended to reduce LDL apoB100 PS compared with the low-MUFA dietary portfolio (228·5% between-diet that adding MUFA to a dietary portfolio of cholesterol-lowering foods provides the added advantage of raising HDL primarily through a reduction in HDL clearance rate. Replacing CHO with MUFA in a dietary portfolio may also lead to reductions in LDL apoB100 concentrations primarily by increasing LDL clearance rate, thus potentiating further the well-known cholesterol-lowering effect of this diet.

Linkage between C-reactive protein and triglyceride-rich lipoprotein metabolism

ObjectiveInflammation plays an important role in atherosclerosis. Elevated C-reactive protein (CRP) levels are associated with a greater risk of cardiovascular disease. Our goal was to study CRP metabolism, and to determine its relationship with lipoprotein metabolism using stable isotope methodology. Material/MethodsEight subjects with combined hyperlipidemia underwent a 15-h primed-constant infusion with deuterated leucine. CRP was purified from the plasma density fraction greater than 1.21g/ml by affinity chromatography. Lipoprotein fractions were separated by sequential ultracentrifugation. Isotope enrichment was determined by gas chromatography/mass spectrometry. ResultsThe subjects had mean LDL-C levels of 147.5mg/dl and mean CRP levels of 3.4mg/l. The mean CRP production rate (PR) was 0.050±0.012mg/kg/day and the mean CRP fractional catabolic rate (FCR) was 0.343±0.056 pools/day (residence time 2.92days). CRP pool size (PS) was significantly related to production (r=0.93; p<0.001), but not FCR. CRP PS was also related to body mass index (r=0.79; p=0.02). There was a significant association between CRP FCR and TRL apoB-100 FCR (r=0.74, p=0.04), as well as between CRP PS and TRL apoB-48 FCR (r=−0.90, p=0.002), indicating linkage between CRP and TRL metabolism. ConclusionThe main determinant of plasma CRP levels was CRP production rate. Moreover a significant linkage between CRP metabolism and both TRL apoB-100 and apoB-48 catabolism was noted.

Lack of association between plasma PCSK9 and LDL-apoB100 catabolism in patients with uncontrolled type 2 diabetes

ObjectivePro-protein convertase subtilisin/kexin type 9 (PCSK9) is a post-transcriptional inhibitor of LDL-receptor. In non-diabetic men, plasma PCSK9 levels were found to be inversely correlated with low-density lipoprotein (LDL) apolipoprotein B100 (apoB) fractional catabolic rate (FCR). Here, we aimed to determine the effect of type 2 diabetes on the association between plasma PCSK9 and FCR of LDL. MethodsA kinetic study of LDL-apoB100, using stable isotopes, was performed in 38 individuals (20 men, 18 women) including 23 non-diabetic normolipidemic subjects and 15 patients with type 2 diabetes. ResultsIn the non-diabetic group, plasma PCSK9 was positively correlated with LDL-C (r=0.64, p=0.001), apoB (r=0.67, p<0.001), and inversely correlated with LDL-apoB FCR (r=−0.61, p=0.002). In contrast, in type 2 diabetic patients, plasma PCSK9 was not associated with LDL-C, apoB and LDL-apoB FCR. However, the lack of association between PCSK9 and LDL-apoB FCR seemed to be limited to the patients with “uncontrolled” diabetes (HbA1c>7%) since a borderline significant negative correlation between PCSK9 and LDL FCR (r=−0.70, p=0.08) was retrieved in patients with HbA1c≤7%. In multivariate analysis, LDL-apoB FCR was independently associated with PCSK9 (p=0.001) and fasting glycaemia (log) (p=0.030) in the non-diabetic population and with PCSK9 (p=0.040) and HbA1c (p=0.029) in diabetic patients. ConclusionOur data indicate that both PCSK9 and glycaemia are independent factors influencing LDL catabolism. Plasma PCSK9 influences significantly the catabolism of LDL-apoB100 in individuals without diabetes, but not in patients with uncontrolled type 2 diabetes. Thus, the influence of diabetes on LDL-apoB FCR catabolism may overwhelm the influence of PCSK9.

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.

Effects of Acute Hyperglucagonemia on Hepatic and Intestinal Lipoprotein Production and Clearance in Healthy Humans

OBJECTIVEThe metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.RESEARCH DESIGN AND METHODSEight healthy men underwent two studies each, in random order, 4–6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).RESULTSThere were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (−39%) and production rate (−30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.CONCLUSIONSGlucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

The effect of apolipoprotein (apo) E genotype on apoB-100 metabolism was examined in three normolipidemic apoE2/E2, five type III hyperlipidemic apoE2/E2, and five hyperlipidemic apoE3/E2 subjects using simultaneous administration of (131)I-VLDL and (125)I-LDL, and multi-compartmental modeling. Compared with normolipidemic apoE2/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased plasma and VLDL cholesterol, plasma and VLDL triglycerides, and VLDL and intermediate density lipoprotein (IDL) apoB concentrations (P < 0.05). These abnormalities were chiefly a consequence of decreased VLDL and IDL apoB fractional catabolic rate (FCR). Compared with hyperlipidemic E3/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased IDL apoB concentration and decreased conversion of IDL to LDL particles (P < 0.05). In a pooled analysis, VLDL cholesterol was positively associated with VLDL and IDL apoB concentrations and the proportion of VLDL apoB in the slowly turning over VLDL pool, and was negatively associated with VLDL apoB FCR after adjusting for subject group. VLDL triglyceride was positively associated with VLDL apoB concentration and VLDL and IDL apoB production rates after adjusting for subject group. A defective apoE contributes to altered lipoprotein metabolism but is not sufficient to cause overt hyperlipidemia. Additional genetic mutations and environmental factors, including insulin resistance and obesity, may contribute to the development of type III hyperlipidemia.

Changes in Apolipoprotein B100-Containing Lipoprotein Metabolism Due to an Estrogen Plus Progestin Oral Contraceptive: A Stable Isotope Kinetic Study

Oral contraceptives with estrogen plus progestin are likely to influence apolipoprotein B (apoB)-containing lipoprotein metabolism by changing the expression of different enzymes or receptors that play a major role in this metabolism. However, the precise changes in apoB kinetic parameters induced by oral contraceptives that are now currently used are unknown. We studied the impact of Moneva, containing 30 microg ethinylestradiol and 75 microg gestodene, on the apoB production rate and fractional catabolic rate of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL). Using a 16-h [(13)C]leucine infusion, we performed an apoB kinetic study in nine normolipidemic women before and 3 months after beginning Moneva. On Moneva, serum triglycerides increased moderately (+12%, P = 0.04) in the fed state, whereas serum LDL remained unchanged. LDL particles were richer in triglycerides in women on Moneva (7.5 +/- 1.5 vs. 4.3 +/- 1.0% of total LDL mass, P < 0.01). The apoB production rate of VLDL, IDL, and LDL increased by 49 (P = 0.04), 55 (P = 0.05), and 51% (P = 0.01), respectively. The fractional catabolic rate of apoB in LDL increased by 36% (P = 0.04). Consequently, the serum LDL apoB pool size remained unchanged (26.49 +/- 6.98 vs. 23.96 +/- 5.37 mg/kg). Oral contraception with ethinylestradiol plus gestodene induces an increase in the production rate of apoB-containing lipoproteins all along the VLDL-->IDL-->LDL cascade. The increased production rate of apoB in LDL is counterbalanced by a higher fractional catabolic rate of apoB in LDL, thus precluding an increase in the concentration of atherogenic LDL particles.

Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III

To determine the relative contribution of obesity and/or insulin resistance (IR) in the development of dyslipidemia in chronic kidney disease (CKD), we investigated the transport of apolipoprotein (apo) B-100 in nonobese, nondiabetic, nonnephrotic CKD subjects and healthy controls (HC). We determined total VLDL, VLDL(1), VLDL(2), intermediate density lipoprotein (IDL), and LDL-apoB-100 using intravenous D3-leucine, GC-MS, and multicompartmental modeling. Plasma apoC-III and apoB-48 were immunoassayed. In this case control study, we report higher plasma triglyceride, IDL-, VLDL-, VLDL(1)-, and VLDL(2)-apoB-100 concentrations in CKD compared with HC (P < 0.05). This was associated with decreased fractional catabolic rates [FCRs (pools/day)] [IDL:CKD 3.4 (1.6) vs. HC 5.0 (3.2), P < 0.0001; VLDL:CKD 4.8 (5.2) vs. HC 7.8 (4.8), P = 0.038; VLDL(1):CKD 10.1 (8.5) vs. HC 29.5 (45.1), P = 0.007; VLDL(2):CKD 5.4 (4.6) vs. HC 10.4 (3.4), P = 0.001] with no difference in production rates. Plasma apoC-III and apoB-48 were significantly higher in CKD (P < 0.001) and both correlated with impaired FCRs of VLDL, VLDL(1), and VLDL(2) apoB-100 (P < 0.05). In CKD, apoC-III concentration was the only independent predictor of clearance defects in VLDL and its subfractions. Moderate CKD in the absence of central adiposity and IR is associated with mild hypertriglyceridemia due to delayed catabolism of triglyceride rich lipoproteins, IDL, and VLDL, without changes in production rate. Altered apoC-III metabolism may contribute to dyslipidemia in CKD, and this requires further investigation.

Plasma Proprotein Convertase Subtilisin/Kexin Type 9: A Marker of LDL Apolipoprotein B-100 Catabolism?

Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of LDL metabolism because of its ability to facilitate degradation of the LDL receptor. We investigated the association between plasma PCSK9 concentration and LDL apolipoprotein B-100 (apo B-100) metabolism in men with a wide range of body mass index values. We used GC-MS to study the kinetics of LDL apo B-100 after intravenous administration of deuterated leucine and analyzed the data by compartmental modeling. The plasma PCSK9 concentration was measured by ELISA. Univariate regression analysis revealed the plasma PCSK9 concentration to be significantly and positively correlated with cholesterol (r = 0.543; P = 0.011), LDL cholesterol (r = 0.543; P = 0.011), apo B-100 (r = 0.548; P = 0.010), and LDL apo B-100 concentrations (r = 0.514; P = 0.023), and inversely correlated with the LDL apo B-100 fractional catabolic rate (FCR) (r = -0.456; P = 0.038). The association between plasma PCSK9 concentration and the LDL apo B-100 FCR remained statistically significant after adjusting for age, obesity, plasma insulin, homeostasis model assessment score, and dietary energy; however, this association had borderline significance after adjusting for plasma lathosterol. In men, variation in plasma PCSK9 concentration influences the catabolism of LDL apo B-100. This finding appears to be independent of obesity, insulin resistance, energy intake, and age.

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.

Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins

Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.

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.