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Biomedical subjects

J Davignon

Publications and source records attributed to J Davignon.

At least 235 records · Page 13Linked to original sources
PubMed1969

The interaction of cholesterol absorption and cholesterol synthesis in man.

The total miscible pool of cholesterol in the body is determined largely by the interaction of cholesterol absorption and synthesis. In the present study we have examined the net effects of this interplay in one normal and five hypercholesteremic subjects when various amounts of cholesterol were made available for absorption. Feeding large amounts of cholesterol to the normocholesteremic patient caused an expansion of body pools by as much as 20 g before the amount of cholesterol re-excreted as fecal neutral steroids each day came into balance with the cholesterol absorbed from the diet. There was no detectable decrease in total body synthesis of cholesterol nor any increase in conversion of cholesterol into bile acids. However, feedback control of cholesterol synthesis was demonstrable when large quantities of plant sterols were fed: in the hypercholesteremic patients thus studied, the absorption of both endogenous and exogenous cholesterol was then greatly reduced, and a compensatory increase in synthesis occurred. Thus, the plant sterol experiments, but not the cholesterol feeding experiment, demonstrated that feedback control by dietary cholesterol does occur in man. That feedback control by dietary cholesterol is relatively unimportant in man seems to be due to the fact that in the metabolic "steady state" the absorption mechanism is essentially saturated by the large amounts of endogenous cholesterol available for reabsorption. These findings demonstrate that there are important differences between man and various laboratory animals in regard to the interaction of absorption and synthesis as factors controlling the size of tissue pools of cholesterol.

Adult↗
PubMed1968

Usefulness of chromic oxide as an internal standard for balance studies in formula-fed patients and for assessment of colonic function.

In 35 patients maintained solely on liquid formula diets, chromic oxide has been evaluated as an internal standard for balance studies that require stool collections. In 28 patients the excretion of chromic oxide was ideal: steady states were attained in which mean daily output was 90% (or more) of mean daily intake. In these patients corrections for fecal flow could validly be applied.In patients who excreted the marker ideally, the availability of chromic oxide balance data made possible the calculation of pool sizes and turnover rates of unexcreted intestinal content. These indexes bore little relationship to the usual clinical descriptions of bowel habits. In some patient who had daily bowel movements, pool sizes were very large and daily turnover was small, i.e., a large proportion of the colonic contents was not excreted for surprisingly long periods. It is critically important for investigators to recognize this possibility when carrying out balance studies for fecal constituents that may be altered by bacterial action within the gut lumen: for instance, in 6 patients a significant inverse correlation was found between daily fecal turnover and degradative losses of large amounts of dietary beta-sitosterol.7 of 35 patients failed to attain the ideal steady state of chromic oxide excretion. These patients would not have been singled out if an internal standard had not been used. In such patients balance studies that require analysis of fecal constituents must be interpreted with great caution, since the constituents in question may be handled in the same nonideal fashion as the internal standard.

Journal Article↗
PubMedDate not supplied

Apolipoprotein E polymorphism association with lipoprotein profile in endogenous hypertriglyceridemia and familial hypercholesterolemia.

Apolipoprotein (apo) E polymorphism was among the first-reported genetic polymorphisms that explained part of the normal variation in plasma cholesterol concentrations in humans. The aim of this study was to assess the influence of allelic variation at the apo E gene locus on the plasma lipoprotein profile in hyperlipidemia. The lipoprotein levels of hyperlipidemic subjects of the major apo E phenotypes (E3/2, E3/3, and E4/3) were compared. One hundred eighty-two subjects with endogenous hypertriglyceridemia and 98 subjects with familial hypercholesterolemia due to a 10-kb deletion in their low density lipoprotein (LDL) receptor genes were compared with 424 normolipidemic controls from the same environmental background. LDL concentrations were lower in the E3/2 subset than in the E3/3 or E4/3 subset in the control, hypertriglyceridemic, and familial hypercholesterolemic groups. In absolute values, the magnitude of the effect was greatest in the familial hypercholesterolemic group. However, the direction and percentage change were identical in the presence or absence of the LDL receptor defect, indicating that the apo E phenotype effect is independent of LDL receptor status. Triglyceride and very low density lipoprotein (VLDL) cholesterol concentrations were higher in E3/2 than in E3/3 or E4/3 hypertriglyceridemic subjects, but this difference was not found in the familial hypercholesterolemic or control group. Thus, there seems to be a specific interaction between apo E isoforms and VLDL metabolism in hypertriglyceridemia; allelic variation at the apo E gene locus seems to be associated with specific alterations in the plasma lipoprotein profile of subjects with well-defined types of hyperlipidemia.

Adult↗
PubMedDate not supplied

Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health.

Five-hundred seventy-five white-collar workers (374 men; 99% Caucasians) aged 20-59 years were selected on the basis of their being healthy and clinically free from cardiovascular risk factors (except smoking and family history). We have observed a higher relative frequency of the epsilon 3 allele in this population, as is true of populations with a low prevalence of coronary heart disease. Each of the 11 plasma lipid and lipoprotein traits studied was adjusted for age, weight, height, body mass index, plasma glucose, and uric acid in men and women separately. The influence of each of the three common apo E alleles on each adjusted trait was evaluated by use of the average excess statistic. We established that in a population selected for health, the epsilon 2 allele is associated with lower plasma levels of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B associated with LDL cholesterol in both men and women. Conversely, the epsilon 4 allele is associated with higher levels of these traits in women only. In contrast to the findings in populations not selected for health, the presence of the epsilon 2 allele in our subjects tended to be associated with lower and the epsilon 4 allele with higher plasma triglyceride levels. Finally and of particular note, the influence of the apolipoprotein E polymorphism on plasma measures of LDL metabolism is different in men and women. Specifically, the influence of the epsilon 4 allele is of greater magnitude in women. A part of this gender difference in allele effects on LDL metabolism in women is associated with the use of oral contraceptives and postmenopausal hormone replacement therapy.

Adult↗
PubMedDate not supplied

Fish oil supplementation reduces beta-very low density lipoprotein in type III dysbetalipoproteinemia.

beta-Very low density lipoproteins (beta-VLDLs) are atherogenic, cholesterol-rich chylomicron and VLDL remnants that accumulate in the plasma of type III dysbetalipoproteinemic subjects. To evaluate the effect of fish oil supplementation on plasma beta-VLDL concentrations, we compared the lipid and lipoprotein responses in nine type III and nine type IV hyperlipidemic subjects. Each individual received 6 g/day omega-3 fatty acids for 12 weeks. Before treatment, the mean total cholesterol, total triglyceride, VLDL triglyceride, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol levels were not different between groups. Conversely, VLDL cholesterol, intermediate density lipoprotein (IDL) cholesterol, and IDL triglycerides were higher in type III than in type IV subjects. Fish oil supplementation was associated with significantly lower levels of cholesterol (-50%), triglycerides (-50%), and apolipoprotein B (-50%) in the d less than 1.006 g/ml ultracentrifugation plasma fraction in both groups, compatible with a reduction in VLDL in type III and type IV subjects, and in beta-VLDL in type III subjects. This finding was confirmed by analysis of the plasma zonal ultracentrifugation profile and the agarose gel electrophoretic pattern of lipoproteins, which showed a reduction in but not a disappearance of remnant particles, suggesting that not all beta-VLDL had been cleared after treatment. The levels of IDL cholesterol and IDL triglycerides (1.006 less than d less than 1.019 g/ml) were not affected in either group. Initially low LDL cholesterol (1.019 less than d less than 1.063 g/ml) and HDL cholesterol levels rose significantly in both groups. In type III hyperlipidemics, all LDL cholesterol values remained below 120 mg/dl, whereas they were higher than 150 mg/dl after treatment in two individuals with type IV hyperlipidemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Interaction of two lipid disorders in a large French-Canadian kindred.

This study investigates the pedigree of 508 individuals over five generations identified by an individual with hypertriglyceridemia, familial hypercholesterolemia, and a IIb lipoprotein electrophoretic phenotype. The sample of 378 living individuals studied extensively for risk factors and disease status was distributed among maternal (170) and paternal (176) relatives and the codescendants (32) of the index case. It was found that the distributions of the plasma lipid and lipoprotein abnormalities in the different subsets of the kindred were consistent with the presence of two separate hereditary lipid disorders: familial hypercholesterolemia on the paternal side and familial hyperprebetalipoproteinemia on the maternal side. This combination of disorders with a possible contribution from factors influencing glucose metabolism was associated with high frequency of hypercholesterolemia and its clinical manifestations and of cardiovascular morbidity among the codescendants. An interaction effect is suggested as an explanation for the unusually high prevalence of hyperlipidemia among the codescendants and for the presence of a IIb phenotype in the index case.

Canada↗
PubMedDate not supplied

Apolipoprotein B-48 and B-100 very low density lipoproteins. Comparison in dysbetalipoproteinemia (type III) and familial hypertriglyceridemia (type IV).

A protein band having the same migration as apolipoprotein (apo) B-48 was observed by SDS electrophoresis in the plasma very low density lipoprotein (VLDL) from 14 Type IV and three Type III hyperlipoproteinemic subjects and from six normal fasting subjects. The VLDL from five Type IV, three Type III, and one normal subject were separated into two subfractions, retained and nonretained, by immunoaffinity chromatography on monoclonal anti-apo B-100 Sepharose. Based on results of electrophoresis and radioimmunoassay, we have concluded that these two fractions represent apo B-48 and apo B-100 lipoproteins that we have named apo B-48 and apo B-100 VLDL. When compared to their respective apo B-100 VLDL, the apo B-48 VLDL from either Type III or Type IV was principally enriched in total lipids, in apo E, and had an electrophoretic migration similar to chylomicrons. This suggests that apo B-48 VLDL has the same origin (i.e., intestinal) in the two disorders. Both apo B-48 and apo B-100 VLDL were enriched in cholesteryl ester (CE) and depleted in triglyceride (TG) in Type III; however, both fractions were rich in TG and poor in CE in Type IV and in normal subjects. In addition, compared to their respective apo B-100 VLDL, the apo B-48 fraction was enriched in CE in Type III and in TG in Type IV. We conclude that, despite a possible similar origin for apo B-48 VLDL in Type III and in Type IV subjects, the composition of apo B-48 VLDL is variable and the CE/TG ratio is more characteristic of the type of hyperlipidemia than of the particular VLDL subfractions.

Adult↗
PubMedDate not supplied

Apo E allele frequency in primary endogenous hypertriglyceridemia (type IV) with and without hyperapobetalipoproteinemia.

Apolipoprotein E polymorphism is responsible for the existence in the population of six apo E phenotypes determined by three alleles acting at a single gene locus. We have previously reported an enrichment in the epsilon 2 allele and the E2-bearing phenotypes in an unselected sample of subjects with primary hyperlipidemia consisting mainly of endogenous hypertriglyceridemia (Type IV). A study was carried out on 214 Type IV hypertriglyceridemic subjects to determine whether there was the same distribution in subjects with hyperapobetalipoproteinemia as in those without. The study showed that the relative enrichment in the epsilon 2 allele was associated only with Type IV subjects without hyperapobetalipoproteinemia. Since hyperapobetalipoproteinemia is a presumed marker for familial combined hyperlipidemia (FCHL), this finding may provide further evidence that FCHL and familial hypertriglyceridemia, both associated with a Type IV lipoprotein pattern, are truly separate disease entities.

Adult↗
PubMedDate not supplied

Apolipoprotein E polymorphism and atherosclerosis.

The apo E locus contributes to determining the variation in plasma cholesterol levels of healthy and diseased populations. It also influences the expression of hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a complex multifactorial interaction. There is evidence that the presence of apo E2 is protective, whereas that of apo E4 predisposes to coronary artery disease. The burden of proof, however, lies on future, well-designed clinical trials and prospective studies. The study of the biological significance of the apo E polymorphism in humans has emphasized the importance of gene-gene and gene-environment interactions in the pathogenesis of hyperlipidemia and atherosclerosis. The apo E polymorphism involves the coding region of the apo E gene and results in alterations of the gene product which, in turn, either directly or secondarily affect the metabolic fate of the lipoprotein particles. Rapid advances in knowledge over the last decade have provided a metabolic explanation for the observation of the opposite effects of the epsilon 4 and the epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity which results in delayed clearance of apo E2-bearing lipoprotein particles from plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is degraded more rapidly than apo E3, and may enhance the catabolism of E4-bearing particles, leading to other alterations in lipoprotein metabolism which result in elevated levels of LDL. In view of the significant opposite impacts of the epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is evident that determination of the apo E phenotype will become a useful adjunct to the assessment of the cardiovascular risk profile of an individual. In addition, the relationship between the epsilon 2 allele and type III hyperlipoproteinemia provides a valuable model for the study of complex genetic interactions in the pathogenesis of hyperlipidemia. The further study of apo E and its interactions shows great promise for a deeper comprehension of the pathogenesis of atherosclerosis.

Alleles↗
PubMedDate not supplied

Expression of apolipoprotein B epitopes in lipoproteins. Relationship to conformation and function.

The immunochemical properties of apolipoprotein (apo) B have been studied in very low density lipoprotein (VLDL)1 (Sf 100 to 400), VLDL2 (Sf 60 to 100), VLDL3 (Sf 20 to 60), different intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) subfractions isolated from patients with type IV hypertriglyceridemia. In these lipoproteins, we characterized the association of apo B with other apolipoproteins and the expression and immunoreactivity of several apo B epitopes close to the apo B receptor binding sites (3F5, 4G3, 3A8, and 5E11) and of other epitopes located on the apo B100-B48 common region (1D1 and 2D8). Immunoprecipitation showed that the proportion of lipoprotein particles expressing each apo B epitope increased from VLDL1 to LDL2; this was more apparent with 3A8 and 5E11 than with 3F5. The VLDL that were negative for apo E epitopes (60% or more of the total) were enriched in apo C. The lipoprotein particles containing apo E and/or apo C-III decreased progressively from VLDL1 (30% and 85%, respectively) to LDL2 (10% and 25%, respectively). Similar observations were made for apo C-I and apo D, demonstrating that apolipoprotein heterogeneity is greatest in the lightest lipoproteins. By competitive radioimmunoassay, the epitope for 4G3 was equally immunoreactive in each lipoprotein subclass, and the affinity constant (Ka) of 4G3 for different lipoproteins showed little variation. In contrast, both immunoreactivity and Ka of 3A8 and 5E11 increased progressively and significantly with the increasing density of the lipoprotein subclasses. This phenomenon is correlated with the increasing binding affinity of apo B in these lipoprotein subclasses to the LDL receptor of fibroblasts. We conclude that, as the apo B-containing lipoproteins become smaller, the conformation of specific regions of apo B is modified: in the receptor binding domain, the conformation of epitope 4G3, which is mapped between residues 2980 and 3080, remains constant, while that of 3A8 and 5E11 (residues 3441 to 3568) changes progressively. We propose the theory that the change in conformation in the domain spanning residues 3441 and 3568 allows the maximum expression of epitopes 3A8 and 5E11 and of the receptor binding site.

Adult↗
PubMedDate not supplied

Apolipoprotein E2(Arg158----Cys) frequency in a hyperlipidemic French-Canadian population of apolipoprotein E2/2 subjects. Determination by synthetic oligonucleotide probes.

An underlying cause of type III hyperlipoproteinemia is the presence of variant forms of apolipoprotein (apo) E that are defective in binding to apo B,E low density lipoprotein receptors. This disorder is associated almost exclusively with the apo E2/2 phenotype. However, structural and functional heterogeneity have been demonstrated within this phenotype. The apo E2(Arg158----Cys) variant, displaying 1% of normal apo E3 binding activity, is the most defective known form. In this study, we describe a method in which a pair of 19-mer synthetic oligonucleotide probes were used to distinguish between DNA coding for arginine or cysteine at position 158 in apo E. The specificity of the probes was demonstrated by using DNA from subjects whose apo E protein sequence or phenotype was known. The probes were used to screen a French-Canadian population of 34 apo E2/2 subjects to determine the frequency of the apo E2(Arg158----Cys) variant. All 34 subjects, most of whom displayed clinical or biochemical features of type III hyperlipoproteinemia, were found to be homozygous for apo E2(Arg158----Cys), strongly suggesting that this variant is the most common form of apo E2 within this ethnic and clinical population. In addition, the utility of this approach in detecting new apo E mutants was demonstrated when DNA from one of the apo E3/3 control subjects, whose family has a history of hyperlipidemia and coronary artery disease, reacted with both probes. This result suggests that this subject is heterozygous for normal apo E3 and a new apo E3 variant that is likely to be functionally equivalent to apo E2(Arg158----Cys).

Adult↗