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Biomedical subjects

P H Barrett

Publications and source records attributed to P H Barrett.

At least 19 recordsLinked to original sources
PubMed2002

High-density lipoprotein metabolism in familial hypercholesterolaemia: significance, mechanisms, therapy.

AIM: To assess the significance, mechanisms and therapy of impaired high-density lipoprotein (HDL) metabolism in patients with heterozygous familial hypercholesterolaemia (FH). METHODS: Review of epidemiological, metabolic and clinical literature with synthetic analysis of data referring to HDL. PRINCIPAL FINDINGS AND SYNTHESIS: Low HDL is a powerful risk factor for coronary artery disease (CAD) in FH. Low HDL in FH is a metabolic sequel of insulin resistance, which is the central feature of the visceral accumulation of adipose tissue acquired in later life. Insulin resistance increases hepatic secretion of triglycerides that subsequently results in remodelling of holo-HDL particles and enhanced catabolism of apolipoprotein A-I. Gene-gene and gene-environment interactions may contribute to the pathogenesis of low HDL in FH. Low HDL may also point to other cardiovascular risk factors, such as hyper-remnantaemia, increased small dense low-density lipoproteins (LDL), procoagulopathy and vascular insulin resistance. Visceral obesity should be vigorously identified and treated in FH. Judicious addition of fish oils, niacin and fibrates to a statin may be required to optimise HDL metabolism. Extracorporeal removal of LDL cholesterol should aim not to extract HDL from plasma. CONCLUSIONS: With the increasing incidence of obesity in the community, the metabolic syndrome will overmanifest in patients with FH. Impaired HDL metabolism is an important consequence of this syndrome for FH patients, because it will per se or in collusion with other associated risk factors accelerate the progression of atherosclerosis and CAD. Dysregulation of HDL metabolism principally results from hepatic insulin resistance and remodelling of HDL particles. Obesity should be prevented and aggressively treated in FH and use of a safe combination drug regimen considered to correct the dysmetabolism of HDL in these patients.

Body Composition↗
PubMed2001

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test.

Chylomicron remnant metabolism was studied using a stable isotope breath test in 25 patients with familial hypercholesterolaemia (FH) (10 homozygotes, 15 heterozygotes), and in 15 normolipidaemic controls. A lipid emulsion mimicking the composition of chylomicron remnants and labelled with cholesteryl (13)C-oleate was injected intravenously; (13)CO(2) was measured subsequently in breath using isotope-ratio mass spectrometry. The fractional catabolic rate (pools/h) of the emulsion, derived from a compartmental model, did not differ significantly among the groups: homozygous FH mean 0.20 (S.E.M. 0.05), heterozygous FH 0.12 (0.02), controls 0.16 (0.03). We suggest that the catabolism of chylomicron remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDL receptors.

Adult↗
PubMed2001

Preliminary experience with a new stable isotope breath test for chylomicron remnant metabolism: a study in central obesity.

We aimed to investigate the metabolism of chylomicron remnants in the postabsorptive state employing a new stable isotope breath test in centrally obese men without overt hyperlipidaemia. Groups of 12 centrally obese and 12 non-obese men of similar age and with similar plasma cholesterol and triacylglycerol (triglyceride) levels were studied. The catabolism of chylomicron remnants was measured using an intravenous injection of a remnant-like emulsion containing cholesteryl [(13)C]oleate. Isotopic enrichment of (13)CO(2) in breath was determined using isotope-ratio mass spectrometry, and a multi-compartmental model (SAAM II program) was used to estimate the fractional catabolic rate (FCR) of the chylomicron remnant-like particles. The plasma concentrations of low-density lipoprotein (LDL)-cholesterol, non-high-density lipoprotein (HDL)-cholesterol and insulin were significantly higher (P<0.05) in the obese than the control subjects. The obese subjects had significantly lower HDL-cholesterol (P<0.05) and, in particular, a decreased FCR of the remnant-like particles compared with lean subjects (0.061+/-0.014 and 0.201+/-0.048 pools/h respectively; P=0.016). In the obese group, the FCR of remnant-like particles was inversely associated with the waist/hip ratio, and with plasma triacylglycerol, cholesterol, LDL-cholesterol and non-HDL-cholesterol levels. In multiple regression analysis, the waist/hip ratio was the best predictor of the FCR of the emulsion. In conclusion, this new test suggests that postabsorptive chylomicron remnant catabolism is impaired in centrally obese subjects without overt hyperlipidaemia. This defect may be due to the degree of adiposity.

Adult↗
PubMed2001

Elevated apolipoprotein B-48 and remnant-like particle-cholesterol in heterozygous familial hypercholesterolaemia.

Apolipoprotein B-48 (apoB-48) is a marker of triglyceride-rich lipoprotein (TRL) remnants of intestinal origin. Chylomicron remnants are causally related to atherosclerosis. We have shown previously that fasting plasma apoB-48 may predict postprandial lipaemia. Remnant-like particle-cholesterol (RLP-C) may also reflect TRL remnants. We aimed to determine whether subjects with heterozygous familial hypercholesterolaemia (FH) had an accumulation of remnants of intestinal origin, as reflected by fasting plasma apoB-48 and RLP-C levels. The fasting plasma concentrations of apoB-48 and RLP-C were measured in 15 subjects with heterozygous FH and 15 age- and sex-matched, normolipidaemic subjects. ApoB-48 was determined using SDS-PAGE and a western blotting/enhanced chemi-luminescence technique. RLP-C was measured using an immuno-separation assay. Serum apolipoprotein B-100 (apoB-100) levels were measured using immunonephelometry; lipids were assayed enzymatically. Compared with controls, FH subjects had significantly elevated plasma concentrations of apoB-48 (29.3 median, 16.7-45.1 mg L-1 range vs. 12.8, 7.3-28.6; P < 0.001) and RLP-C (16.2, 1.5-114.3 mg dL-1 vs. 8.5, 5.0-13.5; P = 0.003), as well as serum total apoB-100 (1.9, 1.3-2.6 g L-1 vs. 1.0, 0.3-1.3; P < 0.001), LDL-cholesterol (8.1, 4.6-10.4 mmol L-1 vs. 3.5, 2.4-4.4; P < 0.001) and triglyceride (1.5, 0.6-5.6 mmol L-1 vs. 1.0, 0.4-1.8; P = 0.018). There was no significant difference in HDL cholesterol. The findings suggest that patients with heterozygous FH have elevated plasma concentrations of TRL remnants, including those of intestinal origin. This may be a consequence of decreased clearance of these particles by the LDL-receptor.

Apolipoprotein B-48↗
PubMed2001

Oxidant stress in nephrotic syndrome: comparison of F(2)-isoprostanes and plasma antioxidant potential.

BACKGROUND: The nephrotic syndrome (NS) is associated with an increased risk of coronary heart disease. Increased oxidant stress may contribute to this by means of hyperlipidaemia and/or hypoalbuminaemia. In this study we assessed the contributory role of oxidant stress, as measured by F(2)-isoprostanes and plasma oxygen radical absorbance capacity (ORAC), in subjects with NS. METHODS: We studied 14 subjects with NS and 17 age- and sex-matched healthy non-proteinuric controls. Measurement of plasma and urinary F(2)-isoprostanes was carried out using a combination of silica and reverse-phase cartridges, high-performance liquid chromatography, and gas chromatography mass spectrometry using electron-capture negative ionization. The plasma ORAC assay measured the decrease in fluorescence of phycoerythrin added to plasma in the presence of a free-radical generator. The ORAC value (microM) was calculated as the ratio of the area under the fluorescence decay curve for plasma to the area under the fluorescence decay curve for a Trolox standard. RESULTS: Plasma ORAC was significantly lower in NS patients compared with controls: mean (standard error) NS patients 3306 microM (286); controls 4882 microM (496), P=0.011. In univariate linear regression analysis, plasma albumin was significantly positively correlated with plasma ORAC (r=0.40, P=0.03). Plasma and urinary F(2)-isoprostanes did not differ significantly between NS and control groups. CONCLUSIONS: This study demonstrates that in the NS there is decreased free-radical trapping capacity of plasma that is inversely correlated with hypoalbuminaemia, but no increase in plasma and urinary F(2)-isoprostanes. Decreased total plasma antioxidant potential in combination with hyperlipidaemia may contribute to the increased risk of cardiovascular disease seen in NS.

Absorption↗
PubMed2001

Postprandial dyslipidemia in men with visceral obesity: an effect of reduced LDL receptor expression?

Postprandial lipemia after an oral fat challenge was studied in middle-aged men with visceral obesity. The two groups had similar plasma cholesterol levels, but obese subjects had higher levels of plasma triglyceride and reduced amounts of high-density cholesterol. Fasting plasma insulin was fourfold greater in obese subjects because of concomitant insulin resistance, with a calculated HOMA score of 3.1 +/- 0.6 vs. 0.8 +/- 0.2, respectively. Plasma apolipoprotein B(48) (apoB(48)) and retinyl palmitate (RP) after an oral fat challenge were used to monitor chylomicron metabolism. Compared with lean subjects, the fasting concentration of apoB(48) was more than twofold greater in obese individuals, suggestive of an accumulation of posthydrolyzed particles. After the oral lipid load, the incremental areas under the apoB(48) and RP curves (IAUC) were both significantly greater in obese subjects (apoB(48): 97 +/- 17 vs. 44 +/- 12 microg.ml(-1). h; RP: 3,120 +/- 511 vs. 1,308 +/- 177 U. ml(-1). h, respectively). A delay in the conversion of chylomicrons to remnants probably contributed to postprandial dyslipidemia in viscerally obese subjects. The triglyceride IAUC was 68% greater in obese subjects (4.7 +/- 0.6 vs. 2.8 +/- 0.8 mM. h, P < 0.06). Moreover, peak postprandial triglyceride was delayed by approximately 2 h in obese subjects. The reduction in triglyceride lipolysis in vivo did not appear to reflect changes in hydrolytic enzyme activities. Postheparin plasma lipase rates were found to be similar for lean and obese subjects. In this study, low-density lipoprotein (LDL) receptor expression on monunuclear cells was used as a surrogate marker of hepatic activity. We found that, in obese subjects, the binding of LDL was reduced by one-half compared with lean controls (70.9 +/- 15.07 vs. 38.9 +/- 4.6 ng LDL bound/microg cell protein, P = 0.02). Because the LDL receptor is involved in the removal of proatherogenic chylomicron remnants, we suggest that the hepatic clearance of these particles might be compromised in insulin-resistant obese subjects. Premature and accelerated atherogenesis in viscerally obese, insulin-resistant subjects may in part reflect delayed clearance of postprandial lipoprotein remnants.

Apolipoprotein B-48↗
PubMed2001

Biglycan, a vascular proteoglycan, binds differently to HDL2 and HDL3: role of apoE.

Lipoprotein retention by vascular extracellular matrix proteoglycans is important in atherogenesis. Proteoglycans bind apolipoprotein (apo)B- and apoE-containing lipoproteins. However, the colocalization of apoA-I and apoE with biglycan in atherosclerotic lesions suggests that vascular proteoglycans also may trap high density lipoproteins (HDLs). Because the major HDL subclasses may be atheroprotective to different degrees, we investigated the role of apoE in mediating HDL(2) and HDL(3) binding to the extracellular vascular proteoglycan, biglycan. ApoE-free HDL(2) and HDL(3) did not bind to purified [(35)S]SO(4)-biglycan, whereas apoE-containing HDL(2) and HDL(3) (HDL+E) did. The extent of binding correlated positively with the apoE content for both HDL(2) and HDL(3), although HDL(2)+E had a 3.5-fold higher affinity than did HDL(3)+E. ApoE on HDL(3) was cleaved into 22- and 12-kDa fragments, whereas apoE on HDL(2) remained intact. These results suggest that the cleaved apoE on HDL(3) results in diminished biglycan binding of HDL(3)+E relative to HDL(2)+E. Reducing positive charges on lysine and arginine residues on HDL+E eliminated biglycan binding, suggesting an ionic interaction. Thus, apoE is an important determinant of HDL binding to extracellular vascular proteoglycans and may play a role in HDL retention in the artery wall.

Apolipoprotein A-I↗
PubMed2001

The contribution of intraabdominal fat to gender differences in hepatic lipase activity and low/high density lipoprotein heterogeneity.

Hepatic lipase (HL) hydrolyzes triglyceride and phospholipid in low and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively), and elevated HL activity is associated with small, dense atherogenic LDL particles and reduced HDL2-C. Elevated HL activity is associated with increasing age, male gender, high amounts of intraabdominal fat (IAF), and the HL gene (LIPC) promoter polymorphism (C nucleotide at -514). We investigated the mechanisms underlying the difference in HL activity between men (n = 44) and premenopausal women (n = 63). Men had significantly more IAF (144.5 +/- 80.9 vs. 66.5 +/- 43.2 cm(2), respectively; P < 0.001), higher HL activity (220.9 +/- 94.7 vs.129.9 +/- 53.5 nmol/mL.min; P < 0.001), more dense LDL (Rf, 0.277 +/- 0.032 vs. 0.300 +/- 0.024; P = 0.01), and less HDL2-C (0.19 +/- 0.10 vs. 0.32 +/- 0.16 mmol/L; P < 0.001) than women. After adjusting for IAF and the LIPC polymorphism, men continued to have higher (but attenuated) HL activity (194.5 +/- 80.4 vs.151.0 +/- 45.2, respectively; P = 0.007) and lower HDL2-C (0.23 +/- 0.11 vs. 0.29 +/- 0.14 mmol/L; P = 0.02) than women. Using multiple regression, HL activity remained independently related to IAF (P < 0.001), gender (P < 0.001), and the LIPC genotype (P < 0.001), with these factors accounting for 50% of the variance in HL activity. These data suggest that IAF is a major component of the gender difference in HL activity, but other gender-related differences, perhaps sex steroid hormones, also contribute to the higher HL activity seen in men compared with premenopausal women. The higher HL activity in men affects both LDL and HDL heterogeneity and may contribute to the gender difference in cardiovascular risk.

Abdomen↗
PubMed2001

The tragedy of the Medicare commons?

Peter Ubel's main conclusion is that physician participation in bedside rationing is essential to controlling healthcare costs. This conclusion is out of step with the current focus of thinking and policy debate within Canada and other countries with universal public healthcare systems. In the Canadian context, collectively we need to better understand the limits and choices in defining the "medicare commons," which occurs at the intersection of the overall level of funding, the range of services provided (comprehensiveness) and the level of access that we are able to provide. This will require a deliberative process that must engage patients/the public at all levels of decision-making. Physicians must accept responsibility to use scarce resources prudently, but this is a collective responsibility and must be exercised in a transparent manner.

Canada↗
PubMed2001

Triglyceride enrichment of HDL does not alter HDL-selective cholesteryl ester clearance in rabbits.

Triglyceride (TG) enrichment of high density lipoprotein (HDL), which occurs in hypertriglyceridemic states, significantly enhances the rate at which HDL apolipoprotein (apo)A-I is cleared from the circulation of healthy humans. In the New Zealand White (NZW) rabbit, a species naturally deficient in hepatic lipase (HL), TG enrichment of HDL requires prior lipolytic modification to enhance apoA-I clearance. However, the effect of TG enrichment of HDL on the subsequent clearance of HDL cholesteryl ester (CE) has not previously been examined in vivo. Therefore, we investigated, in the NZW rabbit, the effect of ex vivo TG enrichment of rabbit HDL (by incubation with human very low density lipoprotein) on the clearance of HDL CE and apoA-I radiolabeled with (3)H-cholesteryl oleyl ether and with (131)I, respectively. In nine experiments, TG enrichment of rabbit HDL resulted in an 87% average increase in HDL TG and a corresponding 31% reduction in HDL CE content. The calculated apoA-I and CE fractional catabolic rates associated with TG-rich versus fasting HDL tracers were not significantly different (apoA-I: 0.119 +/- 0.017 vs. 0.107 +/- 0.024 pools per h, P = 0.68; CE: 0.147 +/- 0.014 vs. 0.114 +/- 0.019 pools per h, P = 0.20). In an animal model deficient in HL, TG enrichment of HDL did not alter the rates of HDL apoA-I or selective CE clearance. Further studies are needed to determine whether, in the presence of HL, TG enrichment of HDL alters selective HDL CE clearance.

Animals↗
PubMed2001

Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test.

We have developed a stable isotope breath test for the assessment of chylomicron remnant metabolism and report the results from the breath test in human subjects selected for disorders of chylomicron or remnant metabolism. In type I hyperlipemia, the phenotype is extreme hypertriglyceridemia due to a lack of lipoprotein lipase activity, which causes the failure of remnant formation. The type III dyslipidemia phenotype is caused by the inefficient removal of chylomicron remnants from plasma, generally because of homozygosity for apolipoprotein E2 alleles. The breath test was predicted to be abnormal in type III hyperlipemia, whereas a priori in type I hyperlipemia defective remnant clearance was not anticipated. Subjects were injected with lipid emulsions prepared with a composition similar to normal chylomicron remnants. The emulsions contained cholesteryl ester incorporating the stable nonradioactive isotope (13)C in the fatty acid moiety. End exhalation breath was collected at intervals after intravenous injection of the remnant-like emulsions and analyzed for (13)C enrichment by isotope-ratio mass spectrometry. Compared with the group of normolipemic men, the fractional catabolic rate of remnants measured by the breath test was significantly decreased (P = 0.006) in subjects with type III dyslipidemia. In the group with type I hyperlipemia, the fractional catabolic rate was not different (P = 0.233) from the control group. Therefore, the underlying capacity for remnant catabolism was normal in this group of markedly hypertriglyceridemic subjects. By short-circuiting the step of lipolysis, the remnant-like emulsion breath test provides direct information about remnant clearance and metabolism, which should assist in investigations of postprandial lipid metabolism.

Adolescent↗
PubMed2001

Dietary n-3 polyunsaturated fat increases the fractional catabolic rate of medium-sized HDL particles in African green monkeys.

We have previously described a novel pathway for the metabolism of HDL subfractions in which small [2 apolipoprotein (apoA-I) molecules per particle] HDL particles are converted in a unidirectional manner outside the plasma compartment to medium (3 apoA-I molecules per particle) or large (4 apoA-I molecules per particle) HDL particles, which are subsequently removed from the circulation by the liver (Colvin et al. 1999. J. Lipid Res. 40: 1782;-1792; Huggins et al. 2000. J. Lipid Res. 41: 384;-394). The purpose of the present study was to determine whether the reduction in concentration of medium HDL in African green monkeys consuming n-3 polyunsaturated versus saturated fat diets resulted from decreased in vivo production or increased catabolism. Tracer small LpA-I (HDL containing only apoA-I) were isolated, without ultracentrifugation, by gel filtration and immunoaffinity chromatography and radiolabeled. After injection, the specific activity of apoA-I in small, medium, and large HDL was determined, and the kinetic data were analyzed using our previously published multicompartmental model for HDL subfraction metabolism. We found a significant reduction of apoA-I concentration in medium HDL in the animals fed n-3 polyunsaturated fat (31.2 +/- 0.7 mg/dl) compared with animals fed saturated fat (85.4 +/- 11.9 mg/dl; P = 0.002). The production rates of apoA-I in small, medium, and large HDL were similar in both diet groups; however, there was a significant increase in the fractional catabolic rate of apoA-I in medium HDL in the animals fed n-3 polyunsaturated fat (2.188 +/- 0.501 pools/day) compared with animals fed saturated fat (0.714 +/- 0.191 pools/day; P = 0.02). We conclude that n-3 polyunsaturated fat reduces HDL cholesterol concentration by increasing the fractional catabolic rate of medium-sized HDL particles in African green monkeys.

Animals↗
PubMed2000

Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes.

AIMS: Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. METHODS: Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles. RESULTS: The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively. CONCLUSIONS: Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect.

Adult↗
PubMed2000

Kinetics of very-low-density lipoprotein apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies.

To further explore the physiology of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P < .001) of the hepatic secretion of apoB, which was higher in the fed state compared with the fasted state (1,819 +/- 188 v 1,046 +/- 61 mg/d, P < .001). In the fed state, apoB secretion increased with age (P = .003) and tended to be higher in men compared with women (P = .0065). The fractional catabolism of VLDL apoB decreased with weight (P = .0038) and was lower in men versus women (8.38 +/- 0.55 v 12.59 +/- 1.65 pools/d, P = .007), as well as patients that were carriers of the E4 allele compared with those who were not carriers of this allele (5.52 +/- 0.49 v 9.58 +/- 0.87 pools/d, P < .001). The VLDL apoB concentration in both the fed and fasted states was dependent on both the rate of hepatic production and fractional clearance of apoB. Plasma cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations in the fasted state were principally determined by the fractional catabolism of VLDL apoB (P< .005). These findings suggest that under physiologic conditions in healthy individuals, the transport of VLDL apoB in plasma is predominantly determined by age, sex, body weight, apoE genotype, and prandial status.

Apolipoprotein B-100↗
PubMed2000

Metastatic renal cell cancer after laparoscopic radical nephrectomy: long-term follow-up.

OBJECTIVE: To assess the risk of metastatic disease in longer-term follow-up of patients undergoing laparoscopic radical nephrectomy with morcellation for renal cell carcinoma (RCC). PATIENTS AND METHODS: We present the findings at follow-up at 13.5 to 70 months (mean 33.4 months) of 57 previously reported patients. Three, all of whom initially had clinical stage N0M0 disease, were found to have metastases. One, who had a clinical stage T3 grade III/IV tumor, developed an asymptomatic recurrence in the renal fossa with associated chest metastasis 14 months postoperatively. The second, who had a clinical stage T2 grade II/IV tumor, developed painful bony lesions and a chest metastasis 20 months postoperatively. The third patient, with a clinical stage T3 grade IV/IV tumor, was found to have a solitary port-side abdominal-wall recurrence with no other evidence of metastatic disease at 25 months. CONCLUSIONS: Longer-term follow-up has demonstrated a 5% (3/57) rate of metastases after laparoscopic radical nephrectomy. In two of these patients, the course was consistent with the natural history of RCC; however, the third had a port-site recurrence. Thus, it behooves us to be meticulous with our technique and to follow patients closely after laparoscopic nephrectomy. Several suggestions are made to reduce the likelihood of port-site recurrence.

Aged↗
PubMed2000

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.

Adult↗