Very Low Density Lipoprotein Apo Research Articles

Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia

BackgroundIn familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG). MethodsA cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects.A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors. ResultsThe variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (β=0.365, p<0.001), insulin (β=0.281, p<0.001), Apo AII (β=0.145, p<0.035), and adiponectin levels (β=−0.255, p<0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles. ConclusionsIn patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.

Dietary medium-chain triglyceride supplementation has no effect on apolipoprotein B-48 and apolipoprotein B-100 kinetics in insulin-resistant men

Medium-chain triglyceride (MCT) supplements are used by clinicians to treat patients with severe hypertriglyceridemia who are at risk of pancreatitis. However, the potential mechanisms underlying the effects of MCT on triglyceride-rich lipoprotein (TRL) metabolism have not yet been thoroughly examined in humans. This double-blind randomized crossover study compared the impact of 4 wk of supplementation with 20 g MCT oil/d or 20 g corn oil/d on the kinetics of apolipoprotein (apo) B-48-containing TRLs and apo B-100-containing very-low-density lipoprotein (VLDL), as well as on the expression of key intestinal genes involved in lipid metabolism in 28 obese, insulin-resistant men. The in vivo kinetics of TRL apo B-48 and VLDL apo B-100 were assessed by using a primed-constant infusion of l-[5,5,5-d3]leucine for 12 h in the fed state. Real-time polymerase chain reaction quantification was performed on duodenal biopsy samples taken at the end of each phase of supplementation. Compared with corn oil, MCT supplements had no significant effect on plasma lipoprotein profile or TRL apo B-48 and VLDL apo B-100 kinetics. Positive correlations were observed between the intestinal expression of several key genes involved in lipoprotein metabolism in a subgroup of participants (n = 16) after MCT supplementation. However, there was no difference between MCT and the corn oil control supplement in the intestinal messenger RNA expression levels of these key genes. These data indicate that short-term supplementation with MCT has a neutral effect on TRL apo B-48 and VLDL apo B-100 kinetics and on the intestinal expression of genes involved in lipid and fatty acid metabolism in men with insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT01806142.

Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome

We examined the effects of fenofibrate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofibrate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations (P < 0.05). Fenofibrate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo (P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR (P < 0.05). Fenofibrate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofibrate was 22% less than that with atorvastatin (P < 0.01). With fenofibrate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofibrate decreased VLDL-apoE concentration by lowering VLDL-apoE production and increasing VLDL-apoE catabolism. By contrast, atorvastatin decreased VLDL-apoE concentration chiefly by increasing VLDL-apoE catabolism. Our study provides new insights into the mechanisms of action of two different lipid-lowering therapies on VLDL-apoE metabolism in MetS.

The hyperenergetic-fed obese dog, a model of disturbance of apolipoprotein B-100 metabolism associated with insulin resistance: kinetic study using stable isotopes

The hyperenergetic-fed beagle dog model of obesity-associated insulin resistance has previously demonstrated lipoprotein abnormalities similar to those of obese insulin-resistant humans. The aim of this study was to check, in the insulin-resistant dog, the mechanism leading to abnormalities in the mass of apolipoprotein B-100 (apo B-100) containing lipoproteins. Six healthy male beagle dogs were overfed with a high-fat diet for 28 ± 2.5 weeks. Obesity was associated with insulin resistance as assessed by the euglycemic hyperinsulinemic clamp technique. The kinetics of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) apo B-100 were recorded in dogs, at healthy and insulin-resistant states, using a primed constant infusion of [5,5,5-D 3]leucine. Isotopic enrichment was measured by gas chromatography–mass spectrometry (GC-MS). A multicompartmental model was used for the analysis of tracer kinetics data. Apolipoprotein B-100 concentration was higher in VLDL (2.8-fold, P < .05) but lower in LDL (2-fold, P < .05) in the insulin-resistant compared to the healthy state. Kinetic analysis showed a higher VLDL apo B-100 production (1.7-fold, P < .05). The fractional catabolic rate of VLDL did not change significantly, but the lipolysis was decreased significantly (3-fold, P < .05). The lower LDL apo B-100 level in insulin-resistant dogs was explained by a higher LDL fractional catabolic rate (2.5-fold, P < .05). The mechanisms leading to hypertriglyceridemia (higher production rate and lower lipolysis of VLDL) in insulin-resistant dogs were similar to those described in the insulin-resistant humans.

THE ANTIPROLIFERATIVE MECHANISM OF CUDRAFLAVONE B ON RAT AROTIC SMOOTH MUSCLE CELLS

Suboptimal lipolysis of very low density lipoproteins (VLDL) due to reduced substrate affinity for lipoprotein lipase (LPL) may contribute to the accumulation of apolipoprotein (apo) B in familial combined hyperlipidemia (FCH) or the characteristic increase in triglyceride-rich lipoproteins in familial hypertriglyceridemia (FHTG). To investigate this hypothesis in detail, the VLDL composition and substrate affinity for lipoprotein lipase was determined in 22 normolipidemic controls, 16 FCH probands, and 12 FHTG subjects. VLDL from FCH subjects were enriched in cholesterol and phospholipid. VLDL from FHTG subjects were enriched in triglycerides, cholesterol and phospholipid. Potential apolipoprotein regulators of LPL activity including apo C-II, apo C-III and apo E were not significantly different between FCH and controls when expressed per VLDL apo B. High apo C-III concentrations were present in FHTG-VLDL, and the apo C-III/E-ratio was significantly higher than in FCH- and control-VLDL. An increase of C-III-0, the desialylated isoform, was observed in FHTG-VLDL. The kinetic indicators for in vitro triglyceride hydrolysis by LPL, KM and VMAX, were not significantly different between the groups. KM values measured in vitro were remarkably and consistently high (1.54 mmol VLDL-TG/l), predicting saturation of LPL when VLDL-TG levels exceed 5.5 mmol/l (2 times KM + 2S.D.). In conclusion, VLDL from individuals with FCH or FHTG are normal substrate for lipoprotein lipase in spite of significant differences in lipid and apolipoprotein composition. The high apo C-III content of FHTG-VLDL supports a role in the expression of hypertriglyceridemia.

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.

Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes

Atorvastatin reduces both plasma cholesterol and triglyceride concentrations in patients with type 2 diabetes, but mechanisms underlying triglyceride decrease and the effect of atorvastatin on high density lipoprotein (HDL) still remain unclear. Apolipoprotein (apo) E plays a crucial role in modulating production and clearance of triglyceride-rich very low density lipoprotein (VLDL). The main effect of apoAI is to modulate HDL metabolism. The aim of this work was to study the influence of atorvastatin on apoAI and apoE kinetics and to determine whether its hypocholesterolemic and hypotriglyceridemic effects could be related to changes in this apolipoprotein metabolism. Plasma VLDL-apoE, HDL-apoE, and HDL-apoAI were studied in seven patients with diabetes with mixed hyperlipidemia using a stable isotope labeling technique ([(2)H3]leucine-primed constant infusion) and monocompartmental model before and after 2 months of treatment with 40 mg/day of atorvastatin. Plasma apoE concentration was significantly reduced (44.1 +/- 19.1 versus 32 +/- 11.6 mg/l, p < 0.05) after treatment. This decrease was associated with a diminution of HDL-apoE concentration (17.46 +/- 6.71 versus 13.37 +/- 6.05 mg/l, p < 0.05) and production rate (0.202 +/- 0.085 versus 0.119 +/- 0.047 mg/kg/day, p < 0.05), whereas an increase in VLDL-apoE concentration (6.44 +/- 2.16 before versus 9.23 +/- 4.02 mg/l after, p < 0.05) and production rate (0.827 +/- 0.367 versus 1.524 +/- 0.664 mg/kg/day, p < 0.05) was observed. No significant difference was observed after treatment for apoAI parameters. We conclude that atorvastatin treatment promotes different apoE distribution between HDL and VLDL, favoring VLDL apoE content. The increased number of apoE per VLDL particle suggests that atorvastatin could enhance the direct catabolism of triglyceride-rich VLDL through apoE receptor pathways.

Effect of Ascorbate on Acrolein Modification of Very Low Density Lipoprotein and Uptake of Oxidized Apolipoprotein E by Hepatocytes

Acrolein modification of apolipoprotein (apo) E in human very low density lipoprotein (VLDL) was suppressed by ascorbate. Acrolein-modified apoE in VLDL was not taken up by human hepatoma cell whereas unmodified apoE in the presence of ascorbate was taken up. These results suggest that ascorbate can play an important role in maintaining proper lipoprotein metabolism by the antioxidant effect.

Effect of L-ascorbic acid on the oxidative modification of apolipoprotein E in human very-low-density lipoprotein.

Antioxidant activity of L-ascorbic acid (AsA) against oxidative modification of apolipoprotein (apo) E in human very-low-density lipoprotein (VLDL) was investigated. The VLDL oxidation induced by peroxyl radicals and peroxynitrite led to lipid peroxidation and oxidative modification of apoE. The binding activity of apoE to heparin was decreased by the oxidative modification. AsA (200, 500, and 1,000 microm) inhibited both the lipid peroxidation and the oxidative modification of apoE. These results suggest that AsA prevents the biological function of apoE in VLDL from the oxidation by free radicals.

Very low-density lipoprotein-apoprotein CI is increased in diabetic nephropathy: Comparison with apoprotein CIII

Recent studies have suggested that apoprotein (apo) CI in very low-density lipoprotein (VLDL) plays an important role in causing hypertriglyceridemia independent of apo CIII, which is associated with coronary heart disease (CHD). Because the incidence of CHD is increased in diabetic patients and is even higher when diabetic nephropathy is developed, we measured apo CI levels in VLDL from type 2 diabetic patients, with various degree of nephropathy, and compared the results with those for healthy controls or nondiabetic patients with chronic renal failure (CRF). This study enrolled healthy control subjects, type 2 diabetic patients with normoalbuminuria, microalbuminuria, overt proteinuria, and CRF on hemodialysis and nondiabetic hemodialysis patients. VLDL (density <1.006) was separated by ultracentrifugation. Then the apo CI, CIII, and B concentrations in VLDL were measured by enzyme-linked immunosorbent assay (ELISA). The apo CI, CIII, and B concentrations in VLDL were respectively 3-, 2-, and 2-fold higher, respectively, in diabetic patients with overt proteinuria than in controls. Hemodialysis patients with diabetic nephropathy had levels of apo CI, CIII, and B in VLDL that were 2.6-, 2.7- and 2-fold higher, respectively, than those in controls. Nondiabetic hemodialysis patients also had a 2.7-fold higher level of VLDL apo CIII, whereas VLDL apo CI and VLDL apo B were not significantly increased. VLDL apo CI was significantly correlated with VLDL apo B independently of VLDL apo CIII level. An increase of VLDL apo CIII is a prominent feature of dyslipidemia in CRF patients, regardless of whether they are diabetic or nondiabetic, whereas an increase of VLDL apo CI is more specific to diabetic nephropathy and is closely associated with an increase of VLDL particle numbers, a new risk factor for CHD.

Effect of alpha-tocopherol on the oxidative modification of apolipoprotein E in human very-low-density lipoprotein.

The oxidative modification of apolipoprotein (apo) E and lipid peroxidation in human very-low-density lipoprotein (VLDL) induced by peroxynitrite and cupric ions in vitro were strongly suppressed by enrichment with alpha-tocopherol (alpha-Toc; 170 microM). Alpha-Toc also suppressed the decrease in the heparin-binding activity of apoE in the VLDL oxidation. These results suggest that alpha-Toc protected apoE in VLDL from oxidative stress.

Apolipoprotein E kinetics: influence of insulin resistance and type 2 diabetes.

Insulin resistance related to obesity and diabetes is characterized by an increase in plasma TG-rich lipoprotein concentrations. Apolipoprotein (apo) E plays a crucial role in the metabolism of these lipoproteins and particularly in the hepatic clearance of their remnants. The aim of this study was to explore apoE kinetics of obese subjects and to determine what parameters could influence its metabolism. Using stable-isotope labelling technique ([(2)H(3)]-leucine-primed constant infusion) and monocompartmental model (SAAM II computer software), we have studied the plasma kinetics of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) apoE in 12 obese subjects (body mass index (BMI) 27.4-36.6 kg/m(2)): Seven were type 2 diabetics (age 47-65 y; HbA1c 7.1-10.2%) and five were non-diabetics (age 40-51 y, HbA1c: 4.9-5.3%). Six of the diabetic subjects were insulin resistant as assessed by insulin sensitivity index (HOMA 2.6-10.0), while non-diabetic subjects were all insulin sensitive (HOMA 1.2-2.1). Plasma VLDL and HDL apoE concentrations were significantly higher in diabetic than in non-diabetic subjects (5.74+/-1.60 vs 1.46+/-1.74 mg/l, P<0.01 and 17.81+/-6.67 vs 9.97+/-3.32 mg/l, P<0.05). These increased levels were associated with significantly higher absolute production rate (APR) of VLDL and HDL apoE (0.714+/-0.343 vs 0.130+/-0.200 mg/kg/day, P<0.01, and 0.197+/-0.087 vs 0.080+/-0.060 mg/kg/day, P<0.05, respectively) while no significant difference was found for fractional catabolic rate (FCR) of VLDL and HDL apoE (3.44+/-1.64 vs 1.97+/-0.84/day and 0.30+/-0.12 vs 0.19+/-0.09/day, respectively). In the whole population, BMI was not correlated with any of apoE kinetic data. HOMA was positively correlated with FCR of VLDL apoE (r=0.64, P<0.05) and tended to be correlated with APR of VLDL apoE (r=0.58, P=0.06). HbA1c was positively correlated with APR and FCR of both VLDL apoE (r=0.91 and 0.78, P<0.01, respectively) and HDL apoE (r=0.66 and 0.69, P<0.05, respectively). Obese diabetics are characterized by elevated VLDL and HDL apoE levels associated with enhancement of VLDL and HDL apoE production rates. Whereas obesity did not influence apoE kinetic parameters in itself, insulin resistance may lead to an increase in VLDL apoE production and fractional catabolic rates. Diabetes and the glycemic control may also specifically influence the kinetics of both VLDL and HDL apoE. All together, these disorders should explain at least part of the increase in VLDL and HDL apoE observed in diabetes.

Insulin suppression of VLDL apo B secretion is not mediated by the LDL receptor

Insulin inhibits hepatic very low density lipoprotein (VLDL) apo B secretion in rats. Current studies test whether the insulin effect is LDL receptor-mediated by examining the effect of insulin on VLDL apo B secretion in hepatocytes derived from Ldlr-/- and control mice. Primary hepatocytes were incubated overnight with media containing 14C-leucine and either 0.1 nM (basal) or 200 nM insulin. Afterwards, secreted VLDL B100 and B48 were quantitated. Insulin reduced 14C-labeled B100 and B48 comparably in control and Ldlr-/- hepatocytes with a 62±12% vs. 59±12% decrease in B100, and a 56±11% vs. 61±9% decrease in B48. Results indicate: (1) mouse hepatocytes respond to insulin by reducing VLDL apo B output; (2) both VLDL B100 and B48 secretion are suppressed; and (3) insulin inhibition of VLDL apo B secretion is retained in Ldlr-/- hepatocytes.

Differential metabolism of human VLDL according to content of ApoE and ApoC-III.

We studied the metabolism of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) particles that did or did not have apolipoprotein E (apoE) in 12 normolipidemic women by endogenously labeling plasma apolipoprotein B. The plasma was separated into bound (E+) and unbound (E-) fractions by use of a monoclonal antibody (1D7), and the fractions were ultracentrifuged to yield E+ and E- subfractions of light and dense VLDL and IDL. VLDL E+ and IDL E+ were produced mainly by the liver. VLDL E+ and IDL E+ had lower fractional catabolic rates and much higher apolipoprotein C-III (apoC-III) content than did the corresponding E- particles. Most light VLDL apoE+ underwent lipolysis to dense VLDL E+ with reduced apoC-III content, which was removed from the circulation without conversion to IDL. In contrast, most light VLDL apoE-, poor in apoC-III, was removed from the circulation, and a smaller proportion underwent lipolysis to dense VLDL E-. Most dense VLDL E- underwent lipolysis to IDL E-. The rate constant for lipolysis of dense VLDL to IDL was greater for E- than for E+, and the rate constant for clearance from plasma was greater for dense VLDL E+ than for E-. In conclusion, metabolism of human VLDL particles is influenced by their content of apoE, further modulated by the coexistence of apoC-III.

Postprandial remnant-like lipoproteins in hypertriglyceridemia.

It has been proposed that remnants of chylomicrons and very-low-density lipoproteins (VLDL) are atherogenic. We have used an immunochemical method to isolate remnant-like particles (RLP) and measured them in terms of their cholesterol and triglycerides (TG). RLP consist of apoB-48-containing triglyceride-rich lipoproteins and remnant-like VLDL containing apoB-100. The study aim was to look for information from postprandial RLP data that could not be known from other markers of triglyceride-rich lipoproteins and fasting TG and RLP data alone. A total of 41 subjects were studied. Eight subjects had hypertriglyceridemia (HTG) and low high-density lipoprotein (HDL), 14 had combined hyperlipidemia (CH), 5 had the apo E2/2 genotype receiving gemfibrozil, 10 were normolipidemic (NL) controls, and 4 had hypercholesterolemia. As a whole group, there was correlation among 1) fasting TG, RLP cholesterol (RLP-C), and RLP-TG but not VLDL apo B100, VLDL apo B48 and their respective postprandial responses measured as incremental area under the curve (IAUC), 2) fasting TG and postprandial IAUC of RLP-C and RLP-TG, 3) RLP-C IAUC, RLP-TG IAUC, and TG IAUC, retinyl palmitate (RP) IAUC, and VLDL apo B48 IAUC but not VLDL apo B100 IAUC. The HTG/low HDL-C and CH groups had higher IAUC for RLP-C, RLP-TG, TG, and RP than the NL group. Fasting and postprandial RLP were triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group. The HTG/low HDL-C and CH groups had a delay in their RLP-C but not RLP-TG peaks suggesting a delay in hepatic clearance of RLP and/or a protracted period of lipolysis and/or processing of RLP. The fasting and postprandial RLP-C/RLP-TG and RLP-C/TG ratios were elevated in the apo E2/2 group in spite of gemfibrozil therapy. The increment in postprandial RLP was, however, not exaggerated. Our data indicate that 1) postprandial RLP lipemia is enhanced in HTG subjects when compared with NL subjects, 2) postprandial RLP lipemia is proportional to fasting RLP and TG levels and mirrors, to a large extent, increases in postprandial TG, RP, and VLDL apo B48 but not VLDL apo B100, 3) there are compositional differences in fasting and postprandial RLP in the three forms of HTG studied, RLP being triglyceride enriched in the HTG/low HDL-C group and to a lesser extent in the CH group, and cholesterol-enriched in the apo E2/2 group, and 4) apo E2/2 subjects had high fasting and postprandial RLP-C concentrations in spite of being on treatment with gemfibrozil and having normal fasting and postprandial TG concentrations.

Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects

Apolipoprotein (apo) C-III and apoE play a central role in controlling the plasma metabolism of triglyceride-rich lipoproteins (TRL). We have investigated the plasma kinetics of total, very low density lipoprotein (VLDL) and high density lipoprotein (HDL) apoC-III and apoE in normolipidemic (NL) (n = 5), hypertriglyceridemic (HTG, n = 5), and Type III hyperlipoproteinemic (n = 2) individuals. Apolipoprotein kinetics were investigated using a primed constant (12 h) infusion of deuterium-labeled leucine. HTG and Type III patients had reduced rates of VLDL apoB-100 catabolism and no evidence of VLDL apoB-100 overproduction. Elevated (3- to 12-fold) total plasma and VLDL apoC-III levels in HTG and Type III patients, although associated with reduced apoC-III catabolism (i.e., increased residence times (RTs)), were mainly due to increased apoC-III production (plasma apoC-III transport rates (TRs, mean ± SEM): (NL) 2.05 ± 0.22 (HTG) 4.90 ± 0.81 (P < 0.01), and (Type III) 8.78 mg·kg−1·d−1; VLDL apoC-III TRs: (NL) 1.35 ± 0.23 (HTG) 5.35 ± 0.85 (P < 0.01), and (Type III) 7.40 mg·kg−1·d−1). Elevated total plasma and VLDL apoE levels in HTG (2- and 6-fold, respectively) and in Type III (9- and 43-fold) patients were associated with increased VLDL apoE RTs (0.21 ± 0.02, 0.46 ± 0.05 (P < 0.01), and 1.21 days, NL vs. HTG vs. Type III, respectively), as well as significantly increased apoE TRs (plasma: (NL) 2.94 ± 0.78 (HTG) 5.80 ± 0.59 (P < 0.01) and (Type III) 11.80 mg·kg−1·d−1; VLDL: (NL) 1.59 ± 0.18 (HTG) 4.52 ± 0.61 (P < 0.01) and (Type III) 11.95 mg·kg−1·d−1).These results demonstrate that hypertriglyceridemic patients, having reduced VLDL apoB-100 catabolism (including patients with type III hyperlipoproteinemia) are characterized by overproduction of plasma and VLDL apoC-III and apoE.—Batal, R., M. Tremblay, P. H. R. Barrett, H. Jacques, A. Fredenrich, O. Mamer, J. Davignon, and J. S. Cohn. Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects. J. Lipid Res. 2000. 41: 706–718.

Effects of growth hormone treatment on very-low-density lipoprotein apolipoprotein B100 turnover in adult hypopituitarism

Adult hypopituitarism is associated with hyperlipidemia, mainly due to an increase of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels. Recent studies have shown that such patients exhibit increased hepatic secretion of VLDL apolipoprotein B100 (VLDL apo B100). To examine the effects of growth hormone (GH) replacement on VLDL apo B100 turnover, 13 GH-deficient hypopituitary patients (8 women and 5 men; aged 47 +/- 3 years, mean +/- SEM; body mass index [BMI], 30 +/- 2 kg/m2) entered a double-blind placebo-controlled study for 6 months (GH 0.125 IU/kg/wk for 4 weeks, and then 0.25 IU/kg/wk). GH was subsequently used in all patients for a further 6 months. A 6-hour [1-13C] leucine infusion was administered at baseline and at 6 months. The secretion rate of VLDL apo B100 was derived by kinetic analysis following quantitation of isotopic enrichment by gas chromatography/mass spectrometry. The GH-treated group (6 patients) demonstrated a similar fractional secretion rate (FSR) for VLDL apo B100 at 0 and 6 months. The pool size and absolute secretion rate (ASR) also were unaffected significantly by GH therapy. No significant changes were observed in the placebo group (7 patients). Treatment with GH for 6 months caused an increase in the high-density lipoprotein (HDL) cholesterol concentration (13 patients, 1.27 +/- 0.13 v 1.16 +/- 0.10 mmol/L, respectively, P = .05), whereas total cholesterol and triglyceride concentrations did not change. Nonesterified fatty acids (NEFAs) increased during GH therapy (471 +/- 43 micromol/L at 6 months v 349 +/- 49 micromol/L at baseline, P < .0005). The data suggest that GH does not affect VLDL apo B100 turnover in a significant way.

Action of atorvastatin in combined hyperlipidemia : preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles.

Combined hyperlipidemia (CHL) is characterized by a concomitant elevation of plasma levels of triglyceride-rich, very low density lipoproteins (VLDLs) and cholesterol-rich, low density lipoproteins (LDLs). The predominance of small, dense LDLs contributes significantly to the premature development of coronary artery disease in patients with this atherogenic dyslipoproteinemia. In the present study, we evaluated the impact of atorvastatin, a newly developed inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, on the cholesteryl ester transfer protein (CETP)-mediated remodeling of apolipoprotein (apo) B-containing lipoprotein subspecies, and more specifically, the particle subpopulations of VLDL and LDL in CHL. In parallel, we evaluated the atorvastatin-induced modulation of the quantitative and qualitative features of atherogenic apo B-containing and cardioprotective apo AI-containing lipoprotein subspecies. Atorvastatin therapy (10 mg/d for a 6-week period) in patients with a lipid phenotype typical of CHL (n=18) induced reductions of 31% (P<0.0001) and 36% (P<0.0001) in plasma total cholesterol and LDL cholesterol, respectively. In addition, atorvastatin significantly reduced VLDL cholesterol, triglycerides, and apo B levels by 43% (P<0.0001), 27% (P=0.0006), and 31% (P<0.0001), respectively. The plasma concentrations of triglyceride-rich lipoproteins (VLDL1, Sf 60 to 400; VLDL2, Sf 20 to 60; and intermediate density lipoproteins, Sf 12 to 20) and of LDL, as determined by chemical analysis, were markedly diminished after drug therapy (-30% and -28%, respectively; P<0.0007). Atorvastatin significantly reduced circulating levels of all major LDL subspecies, ie, light (-28%, P<0.0008), intermediate (-27%, P<0.0008), and dense (-32%, P<0.0008) LDL; moreover, in terms of absolute lipoprotein mass, the reduction in dense LDL levels (mean -62 mg/dL) was preponderant. In addition, the reduction in plasma dense LDL concentration after therapy was significantly correlated with a reduction in plasma VLDL1 levels (r=0.429, P=0.0218). Atorvastatin induced a significant reduction (-7%, P=0.0039) in total CETP-dependent CET activity, which accurately reflects a reduction in plasma CETP mass concentration. Total CETP-mediated CET from high density lipoproteins to apo B-containing lipoproteins was significantly reduced (-26%, P<0.0001) with drug therapy. Furthermore, CETP activity was significantly correlated with the atorvastatin-induced reduction in plasma VLDL1 levels (r=0.456, P=0. 0138). Indeed, atorvastatin significantly and preferentially decreased CET from HDL to the VLDL1 subfraction (-37%, P=0.0064), thereby reducing both the levels (-37%, P=0.0001) and the CE content (-20%, P<0.005) of VLDL1. We interpret our data to indicate that 2 independent but complementary mechanisms may be operative in the atorvastatin-induced reduction of atherogenic LDL levels in CHL: first, a significant degree of normalization of both the circulating levels and the quality of their key precursors, ie, VLDL1, and second, enhanced catabolism of the major LDL particle subclasses (ie, light, intermediate, and dense LDL) due to upregulation of hepatic LDL receptors.

Apolipoprotein E polymorphism in men and women from a Spanish population: allele frequencies and influence on plasma lipids and apolipoproteins

The apolipoprotein (apo) E phenotype and its influence on plasma lipid and apolipoprotein levels were determined in men and women from a working population of Madrid, Spain. The relative frequencies of alleles ε2, ε3 and ε4 for the study population ( n=614) were 0.080, 0.842 and 0.078, respectively. In men, apo E polymorphism was associated with variations in plasma triglyceride and very low-density lipoprotein (VLDL) lipid levels. It was associated with the proportion of apo C-II in VLDL, and explained 5.5% of the variability in the latter parameter. In women apo E polymorphism was associated with the concentrations of plasma cholesterol and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) related variables. The allelic effects were examined taking allele ε3 homozygosity as reference. In men, allele ε2 significantly increased VLDL triglyceride and VLDL cholesterol concentrations, and this was accompanied by an increase of the apo C-II content in these particles. Allele ε4 did not show any significant influence on men's lipoproteins. In women, allele ε2 lowered LDL cholesterol and apo B levels, while allele ε4 increased LDL cholesterol and decreased the concentrations of HDL cholesterol, HDL phospholipid and apo A-I. These effects were essentially maintained after excluding postmenopausal women and oral contraceptive users from the analysis. In conclusion: (1) the population of Madrid, similar to other Mediterranean populations, exhibits an underexpression of apo E4 compared to the average prevalence in Caucasians, (2) gender interacts with the effects of apo E polymorphism: in women, it influenced LDL and HDL levels, whereas in men it preferentially affected VLDL, and (3) allele ε2 decreased LDL levels in women, while it increased both VLDL lipid levels and apo C-II content in men, but, in contrast to allele ε4, it did not show an impact on HDL in either sex.

Very—low-density lipoprotein apolipoprotein B100 kinetics in adult hypopituitarism

Hypopituitarism is associated with hyperlipidemia, the mechanisms of which are not fully known. One possible mechanism is an increased hepatic secretion of very—low-density lipoprotein (VLDL) apolipoprotein B100 (apo B100). To investigate this, 13 hypopituitary patients (seven women and six men; age, 46 ± 3 years [mean ± SEM]; body mass index [BMI], 29 ± 2 kg/m 2) and 13 matched controls (seven women and six men; age, 43 ± 3 years; BMI, 28 ± 2 kg/m 2) were investigated in a stable-isotope study. [1- 13C]leucine (1 mg/kg body weight) was administered, followed by a continuous 6-hour infusion of [1- 13C]leucine (at a rate of 1 mg/kg/h). Patients had a similar fractional secretion rate (FSR) of VLDL apo B100 versus controls (0.37 ± 0.05 v 0.38 ± 0.06 pools/h, respectively), but they had a significantly larger pool size (3.4 ± 0.3 v 1.9 ± 0.3 mg/kg) and higher absolute secretion rate ([ASR] 27.8 ± 2.9 v 16.0 ± 2.5 mg/kg/d). The increase in hepatic VLDL production may explain the lipid abnormalities found in hypopituitarism. Fasting circulating nonesterified fatty acids (NEFAs) were decreased in the patients (284 ± 26 v 664 ± 92 μmol/L, P < .001) despite the increase in VLDL secretion. An inverse relationship was observed between the NEFA level and VLDL apo B100 FSR in the patients ( r s = − .85, P < .005).