In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder that may result from different mutations in the apolipoprotein B (apoB) gene or chromosome 2. However, linkage of FHBL to the apoB gene was ruled out in 2 kindreds reported to date, and the genetic and metabolic bases for FHBL remain unknown. One of the reported kindreds is our 40-member F kindred, in which we found linkage of FHBL to a novel susceptibility region on chromosome 3p21. 1-2. In addition to having low apoB levels, some, but not all, of the affected subjects in the F kindred also had low levels of high density lipoprotein (HDL) cholesterol and apoA-I. Our aim was to define the metabolic bases of the disorder in the F kindred. Therefore, we studied the in vivo kinetics of apoB and apoA-I and very low density lipoprotein (VLDL) triglycerides in 4 affected subjects and 5 normolipidemic relatives. Deuterated leucine and deuterated glycerol were used to label the apolipoproteins and triglycerides, respectively. Compartmental modeling was used to obtain the kinetic parameters. Affected subjects had (1) normal fractional catabolic rates (FCRs) for VLDL apoB, (2) increased FCRs for low density lipoprotein (LDL) apoB (0.050+/-0.009 versus 0. 030+/-0.006 pools per hour for normal subjects, P=0.005), and (3) decreased production rates of VLDL apoB (11.4+/-1.7 versus 25.6+/-4. 9 mg. kg(-1). d(-1), P=0.003), LDL apoB (7.8+/-1.3 versus 12.7+/-3.7 mg. kg(-1). d(-1), P=0.04), and VLDL triglycerides (8.2+/-4.5 versus 19.6+/-10.8 58 micromol. kg(-1). h(-1), P=0.09). These data differ from those obtained in previously studied FHBL heterozygotes bearing apoB-2 and apoB-9, 2 very short truncations of apoB. Low HDL cholesterol and apoA-I levels were caused by higher apoA-I FCRs (0. 035+/-0.005 versus 0.018+/-0.005 pools per hour in controls, P<0.01) without significant decrease in apoA-I production rates (18.7+/-2.7 versus 22.8+/-5.6 mg. kg(-1). d(-1)). In conclusion, decreased secretion of apoB-containing lipoproteins and hypercatabolism of LDL account for low apoB and cholesterol levels in this novel form of FHBL.     

Postprandial lipoprotein metabolism in familial hypobetalipoproteinemia

OBJECTIVE: Familial hypobetalipoproteinemia (FHBL) is an autosomal codominantly inherited disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein-cholesterol and apolipoprotein (apo) B. We examined the effect of truncated apoB variants (相似文献   

Human apolipoprotein (Apo) B-48 and ApoB-100 kinetics with stable isotopes

The kinetics of apolipoprotein (apo) B-100 and apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within IDL and LDL were examined with a primed-constant infusion of (5,5,5-(2)H(3)) leucine in the fed state (hourly feeding) in 19 subjects after consumption of an average American diet (36% fat). Lipoproteins were isolated by ultracentrifugation and apolipoproteins by SDS gels, and isotope enrichment was assessed by gas chromatography/mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II. The pool sizes (PS) of TRL apoB-48, VLDL apoB-100, and LDL apoB-100 were 17+/-10, 273+/-167, and 3325+/-1146 mg, respectively. There was a trend toward a faster fractional catabolic rate (FCR) for VLDL apoB-100 than for TRL apoB-48 (6.73+/-3.48 versus 5.02+/-2.07 pools/d, respectively, P=0.06). The mean FCRs for IDL and LDL apoB-100 were 10.07+/-7.28 and 0.27+/-0.08 pools/d, respectively. The mean production rate (PR) of TRL apoB-48 was 6.5% of VLDL apoB-100 (1. 3+/-0.90 versus 20.06+/-6.53 mg. kg(-1). d(-1), P<0.0001). TRL apoB-48 PS was correlated with apoB-48 PR (r=0.780, P<0.0001) but not FCR (r=-0.1810, P=0.458). VLDL apoB-100 PS was correlated with both PR (r=0.713, P=0.0006) and FCR (r=-0.692, P=0.001) of VLDL apoB-100 and by apoB-48 PR (r=0.728, P=0.0004). LDL apoB-100 PS was correlated with FCR (r=-0.549, P=0.015). These data indicate that (1) the FCRs of TRL apoB-48 and VLDL apoB-100 are similar in the fed state, (2) TRL apoB-48 PS is correlated with TRL apoB-48 PR, (3) VLDL apoB-100 PS is correlated with both PR and FCR of VLDL apoB-100 and PR of TRL apoB-48, and (4) LDL apoB-100 PS is correlated with LDL FCR.     

Pediatric gallstone disease in familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is an monogenic co-dominant disorder characterized by reduced plasma levels of cholesterol, low density lipoproteins (LDL) and apolipoprotein B (apoB) often associated with non-alcoholic fatty liver disease (NAFLD). It has been suggested that FHBL might predispose to gallstone disease (GD). We report a hypocholesterolemic 10 year old girl with obstructive jaundice due to cholesterol stones in gallbladder and common bile duct which required cholecistectomy. The analysis of patient's plasma lipoproteins revealed a marked reduction of LDL and apoB, a lipid profile consistent with the clinical diagnosis of heterozygous FHBL. The same profile was found in her mother who had severe NAFLD. The analysis of apoB gene, the main candidate gene in FHBL, revealed that the patient and her mother were heterozygotes for a novel nonsense mutation (Y1220X) predicted to cause the formation of a short truncated apoB (apoB-26.87) not secreted into the plasma. The presence of cholesterol stones could result from increased biliary cholesterol secretion as a compensatory mechanism for the reduced capacity of the liver to export cholesterol incorporated into apoB-containing lipoproteins. FHBL should be considered as a possible predisposing factor for cholesterol gallstones in children (190).     

Genetic variants of ApoE account for variability of plasma low-density lipoprotein and apolipoprotein B levels in FHBL

We report two novel APOB mutations causing short apolipoprotein B (apoB) truncations undetectable in plasma and familial hypobetalipoproteinemia (FHBL). In Family 56, a 5 bp deletion in APOB exon 7 (870_874del5) causes a frame shift, converting tyrosine to a stop codon (Y220X) and producing an apoB-5 truncation. In Family 59, a point mutation (1941G>T) in APOB exon 13 converts glutamic acid to stop codon (E578X), specifying apoB-13. A recurrent mutation in exon 26 (4432delT) produces apoB-30.9 in Family 58. In some members of these families, we observed that plasma low-density lipoprotein (LDL) cholesterol and apoB levels were unusually low even for subjects heterozygous for FHBL. To ascertain whether genetic variations in apolipoprotein E (apoE) would explain some of the variations of apoB and LDL cholesterol levels, apoE genotypes were assessed in affected subjects from a total of eight FHBL families with short apoB truncations. Heterozygous FHBL with the epsilon3/epsilon4 genotype had 10-1 5mg/dL higher plasma LDL cholesterol and apoB levels compared to subjects with the epsilon2/epsilon3 and epsilon3/epsilon3 genotypes. The apoE genotype has been reported to account for approximately 10% of the variation of LDL cholesterol in the general population. It accounted for 15-60% of the variability of plasma LDL cholesterol or apoB levels in our FHBL subjects. The physiologic bases for the greater effects of apoE in FHBL remain to be determined.     

Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity

Overweight individuals with reduced insulin sensitivity often have mild to moderate hypertriglyceridemia. To investigate the role of apolipoprotein (apo)C-III metabolism in the etiology of hypertriglyceridemia in these individuals, we investigated 10 male subjects with different body weights (body mass index, 24-34 kg/m(2)) and insulin sensitivity (homeostasis model assessment, 4.7-35.0). Total plasma and very-low-density lipoprotein (VLDL) apoC-III kinetics, as well as VLDL triglyceride (TG) and VLDL apoB kinetics, were measured with iv injected stable isotopes. The apoC-III, TG, and apoB levels in VLDL ranged from 2.9-18.2 mg/dl, 0.49-2.89 mmol/liter, and 6.7-29.3 mg/dl, respectively. Mean production rates (PRs) were: VLDL apoC-III, 20.2 +/- 4.1 micromol/d (range, 8.0-44.8); VLDL TG, 26.9 +/- 4.6 mmol/d (range, 10.2-51.1); and VLDL apoB, 4.4 +/- 0.8 micromol/d (range, 1.5-9.1). VLDL apoC-III PRs were significantly correlated with body mass index, homeostasis model assessment, and plasma TG (r = 0.66, P < 0.05; r = 0.80, P < 0.01; r = 0.95, P < 0.001, respectively). Similar correlations were found for plasma apoC-III PRs (r = 0.70, P < 0.05; r = 0.67, P < 0.05; r = 0.80, P < 0.01, respectively). Fractional catabolic rates (FCRs) were not significantly related to metabolic variables. VLDL TG levels were strongly related to VLDL apoC-III levels (r = 0.99, P < 0.001) and VLDL apoC-III PRs (r = 0.94, P < 0.001). VLDL apoC-III levels were more strongly correlated with VLDL TG PRs (r = 0.81, P < 0.01) than with VLDL TG FCRs or VLDL apoB FCRs (r = -0.53, P = 0.12; r = -0.37, P = 0.29). These results suggest that increased hepatic production of VLDL apoC-III is characteristic of subjects with higher body weights and lower levels of insulin sensitivity and is strongly related to the plasma concentration and level of production of VLDL TG.     

The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings

The metabolism of apolipoproteins (apo) (a) and B-100 within plasma lipoprotein (a) [Lp(a)] was examined in the fed state in 23 subjects aged 41 to 79 years who received a primed-constant infusion of [5,5,5-2H3] leucine over 15 hours. Lipoprotein (a) was isolated from the whole plasma using a lectin affinity-based method. Apolipoprotein (a) and apoB-100 were separated by gel electrophoresis, and tracer enrichment of each apolipoprotein was measured using gas chromatography/mass spectrometry. Data were fit to a multicompartmental model to determine fractional catabolic rates (FCRs) and secretion rates (SRs). The FCRs of apo(a) and apoB-100 (mean +/- SEM) within plasma Lp(a) were significantly different (0.220 +/- 0.030 pool/d and 0.416 +/- 0.040 pool/d, respectively; P < .001). Apolipoprotein (a) SR (0.50 +/- 0.08 mg/[kg per d]) was significantly lower than that of apoB-100 SR (1.53 +/- 0.22 mg/[kg per d]; P < .001) of Lp(a). Plasma concentrations of Lp(a) were correlated significantly with both apo(a) SR and apoB-100 SR (r = 0.837 and r = 0.789, respectively; P < .001) and negatively with apo(a) FCR and Lp(a) apoB-100 FCR (r = -0.547 and r = -0.717, respectively; P < .01). These data implicate different metabolic fates for apo(a) and apoB-100 within Lp(a) in the fed state. We therefore hypothesize that apo(a) does not remain covalently linked to a single apoB-100 lipoprotein but that it rather reassociates at least once with another apoB-100 particle, probably newly synthesized, during its plasma metabolism.     

Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates

Subjects with moderate combined hyperlipidemia (n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL(1)) apoB (4.52+/-3.06 pools per day on atorvastatin; 5.48+/-4.76 pools per day on simvastatin versus 2.26+/-1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL(1) concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL(1) to VLDL(2) and of VLDL(2) to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54+/-0.30 pools per day at baseline to 1.17+/-0.87 pools per day on atorvastatin and to 0.95+/-0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58-84% by statin treatment (P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22+/-0.04 pools per day) increased to 0.44+/-0.11 pools per day on atorvastatin and 0.38+/-0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.     

Molecular diagnosis of hypobetalipoproteinemia: an ENID review

Primary hypobetalipoproteinemia (HBL) includes a group of genetic disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CRD), with a recessive transmission, and familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the APOB gene. Most mutations in APOB gene cause the formation of truncated forms of apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in APOB gene; therefore, a large proportion of FHBL subjects have no apoB gene mutations or are carriers of rare amino acid substitutions in apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded protein, a proprotein convertase which regulates LDL-receptor number in the liver. Inactivation of this enzyme is associated with an increased LDL uptake and hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop fatty liver disease.     

A high carbohydrate-fat free diet alters the proportion of heparin-bound VLDL in plasma and the expression of VLDL-apoB-100 epitopes

High carbohydrate-fat free diets (CHO-diet) induce the secretion of increased numbers of very-low-density lipoprotein (VLDL) particles and alter the composition and metabolism of VLDL. The aims of this study were to examine VLDL in greater detail, specifically to document any CHO-diet-induced alterations of apolipoprotein B-100 (apoB-100) epitope expression of VLDL, and any changes induced in subclasses of VLDL, as defined by heparin Sepharose chromatography. Fifteen normolipidemic subjects participated in the study by eating a basal typical American diet for 7 days and high carbohydrate diet (85% carbohydrate, less than 1% fat) for another 7 days. The sequence was changed in seven subjects. Fasting blood samples were analyzed for lipoprotein lipid and apoprotein concentrations. Heparin affinity VLDL subclasses were characterized chemically and electrophoretically [sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE)]. Immunoreactivities of apoB in VLDL were tested in solid phase competitive-binding radioimmunoassays (RIAs) using five monoclonal anti-B antibodies that react with defined epitopes of apoB-100. The CHO diet produced consistent increases of plasma triglycerides in all subjects by a mean of 66% and decreases in plasma cholesterol by 18%. ApoB in plasma decreased by 21% and apoA-I by 17%; however, apoE and ApoA-II did not change. VLDL was enriched with triglycerides (55.0% +/- 0.8 v 57.0% +/- 0.7, P less than .05) and apoE (3.7% +/- 0.5 to 5.9% +/- 0.7, P less than .007) and the ratio between apoE and apoC in VLDL increased (0.15 +/- 0.03 to 0.25 +/- 0.03, P less than .002).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of apolipoprotein B metabolism in familial defective apolipoprotein B and heterogeneous familial hypercholesterolemia

Both defective LDL receptors (familial hypercholesterolaemia, FH) and mutations in apolipoprotein B (apoB) on LDL (familial defective apoB, FDB) give rise to a phenotype of elevated LDL cholesterol. We sought to compare the metabolic basis of the two conditions by examining apoB turnover in FDB and FH subjects. A group comprising three heterozygous and one homozygous FDB subjects were compared with five FH heterozygotes and 17 control subjects using a deuterated leucine tracer. Kinetic parameters were derived by multicompartmental modelling. FH heterozygotes had a reduced delipidation rate for VLDL, which led to a moderate increase in plasma triglyceride. Compared with controls and FH, the FDB subjects converted 44% less IDL to LDL. The LDL FCR was reduced to a similar extent in FDB and FH. In all subjects LDL plasma levels appeared to be regulated by the LDL FCR and the rate of production of small VLDL. We conclude that disturbances in IDL metabolism provide the basis for understanding why FDB is less severe than FH. Our findings suggest that an apoB-LDL receptor interaction is important in the IDL to LDL conversion.     

Familial hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease

Introduction. Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disease characterized by abnormally low levels of apolipoprotein-B (apoB) containing lipoproteins. FHBL is caused by APOB, PCSK9 or ANGPTL3 mutations or is associated with loci located in chromosomes 10 and 3p21. However, other genes should be involved. This study describes the kinetic parameters of the apoB containing lipoproteins and sequence abnormalities of the APOB and PCSK9 genes of FHBL patients identified in a large hospital based survey.Material and methods. Cases with primary or secondary causes of hypobetalipoproteinemia were identified. ApoB kinetics were measured in cases with primary forms in whom truncated forms of apoB were not present in VLDL (n = 4). A primed constant infusion of [¹³C] leucine was administered, VLDL and LDL apoB production and catabolic rates measured by a multicompartmental model and compared to normolipemic controls. In addition, these subjects had an abdominal ultrasound and direct sequencing was carried out for the PCSK9 and apoB genes.Results. Three individuals had normal apoB production with increased catabolic rate; the remaining had reduced synthetic and catabolic rates. Various polymorphisms, some of them previously unreported (*), in the PCSK9 gene (R46L, A53V, I474V, D480N^*, E498K^*) and in the apoB gene (N441D^*, Y1395C, P2712L, D2285E^*, I2286V, T3540S^*, T3799M^*) were found in the FHBL patients. We found hepatic ultrasound changes of hepatic steatosis in only one of the four probands. Conclusion. FHBL without truncated apoB is a heterogeneous disease from a metabolic and a genetic perspective. Hypobetalipoproteinemia is a risk factor but not an obligate cause of steatosis.     

Apolipoprotein B-100 kinetics in visceral obesity: associations with plasma apolipoprotein C-III concentration

Obesity is strongly associated with dyslipidemia, which may account for the associated increased risk of atherosclerosis and coronary disease. We aimed to test the hypothesis that kinetics of hepatic apolipoprotein B-100 (apoB) metabolism are disturbed in men with visceral obesity and to examine whether these kinetic defects are associated with elevated plasma concentration of apolipoprotein C-III (apoC-III). Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured in 48 viscerally obese men and 10 age-matched normolipidemic lean men using an intravenous bolus injection of d(3)-leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry (GCMS). Kinetic parameters were derived using a multicompartmental model (Simulation, Analysis, and Modeling Software II [SAAM-II]). Compared with controls, obese subjects had significantly elevated plasma concentrations of plasma triglycerides, cholesterol, LDL-cholesterol, VLDL-apoB, IDL-apoB, LDL-apoB, apoC-III, insulin, and lathosterol (P <.01). VLDL-apoB secretion rate was significantly higher (P =.034) in obese than control subjects; the fractional catabolic rates (FCRs) of IDL-apoB and LDL-apoB (P <.01) and percent conversion of VLDL-apoB to LDL-apoB (P <.02) were also significantly lower in obese subjects. However, the decreased VLDL-apoB FCR was not significantly different from the lean group. In the obese group, plasma concentration of apoC-III was significantly and positively associated with VLDL-apoB secretion rate and inversely with VLDL-apoB FCR and percent conversion of VLDL to LDL. In multiple regression analysis, plasma apoC-III concentration was independently and significantly correlated with the secretion rate of VLDL-apoB (regression coefficient [SE] 0.511 [0.03], P =.001) and with the percent conversion of VLDL-apoB to LDL-apoB (-0.408 [0.01], P =.004). Our findings suggest that plasma lipid and lipoprotein abnormalities in visceral obesity may be due to a combination of overproduction of VLDL-apoB particles and decreased catabolism of apoB containing particles. Elevated plasma apoC-III concentration is also a feature of dyslipidemia in obesity that contributes to the kinetic defects in apoB metabolism.     

Differences in postprandial concentrations of very-low-density lipoprotein and chylomicron remnants between normotriglyceridemic and hypertriglyceridemic men with and without coronary heart disease

It has been suggested that the postprandial elevation of plasma triglycerides is more closely linked to coronary heart disease (CHD) than the fasting triglyceride level. However, the postprandial situation is complex, as hepatogenous triglyceride-rich lipoprotein (TRL) particles (apolipoprotein [apo]B-100 and very-low-density lipoprotein [VLDL]) are mixed in the blood with apoB-48-containing lipoproteins secreted from the intestine. To analyze the relative proportion of liver-derived and intestinal apoB-containing TRL in subjects with and without CHD, we performed standardized oral fat-loading tests in young survivors of myocardial infarction, a large proportion of whom are hypertriglyceridemic (HTG), as well as sex- and population-matched healthy control subjects. A special effort was made to recruit healthy HTG subjects as controls for the HTG patients. Fasting plasma triglycerides (3.74+/-1.35 v3.01+/-0.83, NS), low-density lipoprotein (LDL) cholesterol, and VLDL lipids, and apoB-100 and apoB-48 content at Svedberg flotation rate (Sf) 60-400, Sf 20-60, and Sf 12-20 did not differ between HTG patients (n = 10) and HTG controls (n = 14). Normotriglyceridemic (NTG) patients (n = 15) had higher fasting plasma triglycerides (1.44+/-0.39 v 0.98+/-0.33 mmol/L, P < .05) and LDL cholesterol (4.07+/-0.71 v 3.43+/-0.64, P < .05) than NTG controls (n = 34). The triglyceride elevation was accounted for by a higher level of small VLDL (apoB-100 in the Sf 20-60 fraction, 52+/-17 v29+/-20 mg/L, P < .05). HTG patients responded with clearly elevated plasma triglycerides in the late postprandial phase, ie, 7, 8, and 9 hours after fat intake. Essentially, this was explained by a retention of large VLDL particles, since HTG patients exhibited no major differences in apoB-48 concentrations in the Sf > 400, Sf 60-400, and Sf 20-60 fractions but showed marked differences in the level of apoB-100 at Sf 60-400 (large VLDL) 9 hours after fat intake when compared with HTG controls (101+/-13 v 57+/-5 mg/L, P < .01). NTG patients were characterized by a more rapid increase of large VLDL in the early postprandial state, ie, 3 hours after fat intake, with a mean increase from baseline to 3 hours of 24.1+/-6.7 mg/L for NTG patients and 11.8+/-2.0 mg/L for controls (P < .05). ApoB-48 levels were also slightly higher, but all TRL parameters returned to baseline within 9 hours after fat intake. In conclusion, elevated triglyceride levels in the postprandial state in CHD patients are explained to a large extent by the accumulation of endogenous TRL. This suggests that the postprandial dyslipidemia encountered in CHD is more dependent on a failure of regulation of endogenous TRL versus the exogenous TRL species.     

Effects of ApoE genotype on ApoB-48 and ApoB-100 kinetics with stable isotopes in humans

Subjects with the apolipoprotein (apo) E4 allele have been shown to have higher low density lipoprotein (LDL) cholesterol and apoB levels than do subjects with the other alleles. To elucidate the metabolic mechanisms responsible for this finding, we examined the kinetics of apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and LDL by using a primed constant infusion of [5,5,5-(2)H(3)]leucine in the fed state (hourly feeding) during consumption of an average American diet in 18 normolipidemic subjects, 12 of whom had the apoE3/E3 genotype and 6, the apoE3/E4 genotype. Lipoproteins were isolated by ultracentrifugation and apolipoproteins, by sodium dodecyl sulfate gels; isotope enrichment was assessed by gas chromatography-mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II software. Compared with the apoE3/E3 subjects, the apoE3/E4 subjects had significantly higher levels of total apoB, 100. 1+/-17.8 versus 135.4+/-34.0 mg/dL (P=0.009), and significantly higher levels of LDL apoB-100, 88.1+/-19.2 versus 127.5+/-32.7 mg/dL (P=0.005), respectively. The pool size of TRL apoB-48 was 17.4% lower for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 33.3% lower production rate (P=0.28). There was no significant difference in the TRL apoB-48 fractional catabolic rate (5.1+/-2.2 versus 5.0+/-2.1 pools per day). The pool size for VLDL apoB-100 was 36% lower for apoE3/E4 subjects compared with apoE3/E3 subjects due entirely to a 30% lower production rate (P=0.04). The LDL apoB-100 pool size was 57.8% higher (P=0.003) for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 35.5% lower fractional catabolic rate of LDL apoB-100 (P=0.003), with no significant difference in production rate. In addition, 77% of VLDL apoB-100 was converted to LDL apoB-100 in apoE3/E4 subjects compared with 58% in apoE3/E3 subjects (P=0.05). In conclusion, the presence of 1 E4 allele was associated with higher LDL apoB-100 levels owing to lower fractional catabolism of LDL apoB-100 and a 33% increase in the conversion of VLDL apoB-100 to LDL apoB-100.     

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

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

Effects of lovastatin therapy on very-low-density lipoprotein triglyceride metabolism in subjects with combined hyperlipidemia: evidence for reduced assembly and secretion of triglyceride-rich lipoproteins.

We have previously reported decreased production rates of the major apolipoprotein B (apoB)-containing lipoproteins, very-low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) in patients with combined hyperlipidemia (CHL) during treatment with lovastatin. In the present study, we determined the effects of lovastatin therapy on VLDL triglyceride (TG) metabolism. Plasma VLDL turnover was determined in six CHL patients, before and during lovastatin therapy. 3H-triglyceride-glycerol-specific activity data derived from injection of 3H-glycerol were analyzed by compartmental modeling. The effects of lovastatin on VLDL TG metabolism were compared with those previously determined on VLDL apoB metabolism in these subjects. Lovastatin therapy was associated with decreased concentrations of VLDL TG in five of six patients and decreased VLDL apoB concentrations in all six. VLDL TG production rates (PR) decreased in five patients, with the mean for the group decreasing from 14.1 +/- 7.1 to 10.3 +/- 4.0 mg/kg/h (P less than .05). VLDL apoB PR also decreased in five patients, with the mean decreasing from 21.8 +/- 20.3 to 12.2 +/- 9.0 mg/kg/d (P = .11). Changes in VLDL TG concentrations during lovastatin treatment were correlated with changes in VLDL apoB concentrations (r = .74, P = .09) and in VLDL TG PR (r = .91, P = .01). Changes in VLDL TG PR were also related to changes in VLDL apoB PR (r = .62, P = NS). There were no consistent changes in the fractional catabolic rates of either VLDL TG or VLDL apoB during lovastatin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apolipoprotein A-I and A-II kinetic parameters as assessed by endogenous labeling with [(2)H(3)]leucine in middle-aged and elderly men and women

The purpose of our study was to investigate high density lipoprotein (HDL) apolipoprotein (apo) A-I and apoA-II kinetics in a state of constant feeding after a primed-constant infusion of [5,5, 5-(2)H(3)]L-leucine in 32 normolipidemic older men and postmenopausal women (aged 41 to 79 years). ApoA-I and apoA-II were isolated from plasma HDL, and enrichment was determined by gas chromatography/mass spectrometry. The fractional secretion rate was obtained by using a monoexponential equation calculated with the SAAM II program (Department of Bioengineering, University of Washington, Seattle). Mean HDL cholesterol (HDL-C) and total triglyceride levels were 23% higher and 27% lower, respectively, in women than in men. Mean plasma apoA-I levels were 10% greater in women than in men, whereas mean apoA-II levels were similar. HDL size, estimated by gradient-sizing gels and by the HDL-C/apoA-I+apoA-II ratio, was significantly higher in women than in men. Mean apoA-I secretion rates (SRs) were similar in men and women (12.28+/-3.64 versus 11.96+/-2.92 mg/kg per day), whereas there was a trend toward a lower (-13%) apoA-I fractional catabolic rate (FCR) in women compared with men (0.199+/-0.037 versus 0. 225+/-0.062 pools per day, P=0.11). Mean apoA-II SRs (2.21+/-0.57 versus 2.27+/-0.91 mg/kg per day) and FCRs (0.179+/-0.034 versus 0. 181+/-0.068 pools per day) were similar in men and women. For the group as a whole, there was an inverse association between the HDL-C/apoA-I+apoA-II ratio and apoA-I FCR and between the ratio and triglyceride levels. Plasma levels of apoA-I and apoA-II were correlated with their respective SRs but not FCRs. These data suggest a major role for apoA-I and apoA-II SRs in regulating the plasma levels of these proteins, whereas apoA-I FCR might be an important factor contributing to the differences in apoA-I levels between men and postmenopausal women. Moreover, plasma triglyceride levels are important determinants of HDL size and apoA-I catabolism.     

Normal production rate of apolipoprotein B in LDL receptor-deficient mice

The low density lipoprotein (LDL) receptor is well known for its role in mediating the removal of apolipoprotein B (apoB)-containing lipoproteins from plasma. Results from in vitro studies in primary mouse hepatocytes suggest that the LDL receptor may also have a role in the regulation of very low density lipoprotein (VLDL) production. We conducted in vivo experiments using LDLR-/-, LDLR+/-, and wild-type mice (LDLR indicates LDL receptor gene) in which the production rate of VLDL was measured after the injection of [35S]methionine and the lipase inhibitor Triton WR1339. Despite the fact that LDLR-/- mice had a 3.7-fold higher total cholesterol level and a 2.1-fold higher triglyceride level than those of the wild-type mice, there was no difference in the production rate of VLDL triglyceride or VLDL apoB between these groups of animals. Experiments were also conducted in apobec1-/- mice, which make only apoB-100, the form of apoB that binds to the LDL receptor. Interestingly, the apobec1-/- mice had a significantly higher production rate of apoB than did the wild-type mice. However, despite significant differences in total cholesterol and triglyceride levels, there was no difference in the production rate of total or VLDL triglyceride or VLDL apoB between LDLR-/- and LDLR+/- mice on an apobec1-/- background. These results indicate that the LDL receptor has no effect on the production rate of VLDL triglyceride or apoB in vivo in mice.