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D S Fredrickson

Publications and source records attributed to D S Fredrickson.

At least 37 records · Page 2Linked to original sources
PubMed1978

Abnormal concentration and anomalous distribution of apolipoprotein A-I in Tangier disease.

A double-antibody radioimmunoassay was used to determine the concentration and distribution of apolipoprotein A-I (apoA-I) in the plasma of patients with Tangier disease. Obligate heterozygotes for Tangier disease had apoA-I levels that were 50% or less of controls, even when estimates of high-density lipoprotein cholesterol concentration were normal. Plasma apoA-I levels in Tangier homozygotes were at most 3% of normal. Most of the apoA-I in the plasma of homozygotes sedimented in the ultracentrifuge at density 1.21 g/ml, and no more than 20% was recovered in the plasma lipoprotein fraction. Radioimmunoassay demonstrated no immunochemical differences between Tangier and control apoA-I.

Adult↗
PubMed1978

Properties of the plasma very low and low density lipoproteins in Tangier disease.

The absence of normal high density lipoproteins (HDL) in Tangier disease is well established, but the properties of very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in this disorder have not been well defined. The profiles obtained by analytic ultracentrifugation and the chemical composition, morphology, and electrophoretic mobility of Tangier and normal VLDL and LDL were compared. Apolipoproteins were fractionated by gel chromatography and characterized by amino acid analysis, polyacrylamide-gel electrophoresis, and immunochemical reactivity. Concentrations of low density lipoproteins of S(f) (o) 0-12 were reduced in three of six Tangier plasmas studied by analytic ultracentrifugation. Accumulation of intermediate density lipoproteins (S(f) (o) 12-20) was not observed. Two subjects with hypertriglyceridemia had normal VLDL (S(f) (o) 20-400) levels, suggesting that abnormalities of chylomicron metabolism probably account for the hypertriglyceridemia frequently observed in this disorder. Tangier VLDL migrate more slowly than normal VLDL on paper electrophoresis, yet their morphology, gross chemical composition, and qualitative apolipoprotein content are similar. Quantitative abnormalities in C-apolipoproteins, however, were observed in Tangier VLDL. When patients were consuming unrestricted diets, C apoproteins accounted for 19-49% of the protein in lipoproteins of d < 1.006 g/ml. Ingestion of low-fat, high-carbohydrate diets reduced the VLDL-C-apoprotein content in all Tangier patients (mean = 17% of VLDL protein vs. 43% in controls). These findings suggested that a major proportion of the C apoproteins in Tangier plasma is associated with chylomicrons or their remnants, perhaps because the C-apoprotein reservoir normally provided by HDL is absent. This secondary mechanism for C-apoprotein conservation is lost when dietary fat is withdrawn.LDL-2 (1.035 < d < 1.063) from Tangier and control plasma had identical electrophoretic mobilities. Tangier LDL-2 had slightly smaller median diameters (210-225 A vs. 230-240 A in controls) and a quite different composition than normal LDL-2. Triglyceride accounted for a mean of 29% of Tangier LDL-2 mass (control = 6%) and the cholesteryl ester content was reduced by about 50%. Thus, HDL may be required for the generation of chemically normal LDL. Alternatively, the fundamental defect in Tangier disease may involve all lipoprotein classes.

Apolipoproteins↗
PubMed1977

Isolation and characterization of an abnormal high density lipoprotein in Tangier Diesase.

The nature of the high density lipoproteins has been investigated in five patients homozygous for Tangier disease (familial high density lipoprotein deficiency). It has been established that Tangier high density lipoproteins, as isolated by ultracentrifugation, are morphologically heterogenous and contain several proteins (Apo B, albumin, and Apo A-II). An abnormal lipoprotein has been isolated from the d = 1.063-1.21 g/ml ultracentrifugal fraction by agarose-column chromatography which contains apoprotein A-II as the sole protein constituent. In negative-stain electron microscopy, these lipoproteins appeared as spherical particles 55-75 A in diameter. By a variety of criteria (immunochemical, polyacrylamide electrophoresis, amino acid composition, and fluorescence measurements), apoprotein A-I the major apoprotein of normal high density lipoproteins and the C apoproteins were absent from this lipoprotein. As demonstrated by (125)I very low density lipoprotein incubation experiments with Tangier plasma, C apoproteins did not associate with lipoproteins of d = 1.063-1.21 g/ml. Tangier apoprotein A-II, isolated to homogeneity by delipidation of the apoprotein A-II-containing lipoprotein or Sephadex G-200 guanidine-HCl chromatography of the d = 1.063-1.21 g/ml fraction, was indistinguishable from control apoprotein A-II with respect to amino acid composition and migration of tryptic peptides in urea-polyacrylamide electrophoresis. The ability of Tangier apoprotein A-II to bind phospholipid was demonstrated by in vitro reconstitution experiments and morphological and chemical analysis of lipid-protein complexes. It is concluded that normal high density lipoproteins, as defined by polypeptide composition and morphological appearance, are absent from Tangier plasma and that as a consequence, the impairment of C apoprotein metabolism contributes to the hypertriglyceridemia and fasting chylomicronemia observed in these patients.

Amino Acids↗
PubMed1976

Research fellowships.

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National Institutes of Health (U.S.)↗
PubMed1976

Lipid, glucose, and insulin interrelationships in normal, prediabetic, and chemical diabetic subjects.

Fasting levels of plasma cholersterol and triglyceride, lipoprotein patterns, and fasting and postintravenous glucose levels of blood glucose, serum insulin, serum growth hormone, and plasma free fatty acids in a genetic potential diabetic population were compared to those in a similar normal control population. THe potential diabetic population was further divided into groups of patients with a normal (prediabetic) or abnormal (chemical diabetic) glucose tolerance test. Although no clear-cut lipid differences were noted, certain trends appeared. More type IV hyperlipoproteinemia was seen in male prediabetic (21%) and male chemical diabetic patients (19%) than in normal male subjects (5%); in female subjects only a few type IV patterns were seen. Type II hyperlipoproteinemia was not seen in any normal subject, but was noted in nearly 9% of those with chemical diabetes. Fasting cholesterol levels correlated better with age than did fasting triglyceride levels in most of the patient groups. Fasting triglyceride levels showed a significant positive correlation with the serum insulin area of the oral glucose tolerance test in the normals wna prediabetic persons, and also showed a significant positive correlation with the blood glucose area of the prediabetic and chemical diabetic patients. It is suggested that a normal relationship between triglyceride concentration and insulin response to glucose is lost in chemical diabetes. Sex differences were also noted in the inslin response and the insulin-glucose relationships during the oral glucose tolerance test, with normal menstruation women showing a significantly lower insulin-glucose relationship than the age-related men.

Adolescent↗
PubMed1975

Thf complete amino acid sequence of C-I (apoLp-Ser), an apolipoprotein from human very low density lipoproteins.

C-I was prepared from very low density lipoproteins of patients with familial type V hyperliporproteinemia. Peptides from tryptic digests of unmodified and succinylated C-I, chymotryptic peptides, and the products of cayanogen bromide cleavage were isolated and characterized. Sequence analysis of tryptic peptides was performed by the dansyl (5-dimethylaminonaphthalene-1-sulfonyl) technique and hydrolytic regeneration of the amino acid residues from the phenylthiocarbamyl derivatives. Alignment of the tryptic fragments within the cyanogen bromide and succinyl-tryptic peptides was confirmed by the overlap chymotryptic peptides. The complete amino acid sequence of C-I, 57 residues in length, does not reveal any obvious basis for its lipophilic properties.

Amino Acid Sequence↗
PubMed1975

Structural and compositional changes attending the ultracentrifugation of very low density lipoproteins.

The effects of repetitive ultracentrifugation on the physical and chemical properties of very low density lipoproteins (VLDL) were investigated. VLDL recentrifuged one to seven times were characterized by chemical analyses, analytical ultracentrifugation and electron microscopy. The VLDL content of triglyceride was increased and the proportion of phospholipid decreased by ultracentrifugation. Recentrifugation of VLDL decreased the number of Sf-o 20-100 particles and generated particles of Sf-o greater than 400. The bulk of the material removed from VLDL by ultracentrifugation was lipoprotein having pre-beta mobility on paper electrophoresis, flotation rates of Sf-o 10-100 and a particle size of 300-400 A-O. Two ultracentrifugations separated an average of 14% of the starting VLDL protein. Characterization of the apoproteins in this material by polyacrylamide gel electrophoresis, gel chromatography, immunoprecipitation and amino acid analysis demonstrated a relatively high proportion of beta-apoprotein and relatively little C-apoproteins.

Adult↗
PubMed1975

Type III hyperlipoproteinemia: an analysis of two contemporary definitions.

Two current definitions of type III hyperlipoproteinemia, "floating beta" lipoproteins and an estimate of the relative content of cholesterol and triglyceride in lipoproteins of density less than 1,006 (very low-density [VLD] lipoproteins), have been compared. Over 3100 complete lipoprotein analyses of 182 adults with primary familial hyperglyceridemia, covering a wide range of plasma lipid concentrations, formed the data base for this retrospective analysis: The ratio of VLD lipoprotein cholesterol to the plasma triglyceride concentration (VLDL/TG=r) proved capable of segregating an apparently unique subpopulation with persistently abnormal very low-density lipoprotein composition. Although floating beta lipoproteins were present in nearly all patients with a high r value, they also appeared inconsistently in many other patients. It is concluded that the chemical index to VLD lipoprotein composition is the better, albeit, temporary definition for this disorder. When the plasma triglyceride concentration is between 150 and 1000 mg/100 ml, an r not less than 0.25 should be considered as suggestive and a value not less than 0.30 as diagnosttc of type III hyperlipoproteinemia.

Adult↗
PubMed1975

The biochemical, clinical, and genetic features of type III hyperlipoproteinemia.

The clinical and biochemical features of type III hyperlipoproteinemia are described in 49 patients from 23 to 70 years of age. An increase in very low-density lipoproteins (VLDL) of abnormal chemical composition was the basis for diagnosis. The untreated patients all had hypercholesterolemia and hyperglyceridemia, and, on the average, decreased concentrations of both low- and high-density lipoproteins. Seventy-four percent had xanthomas, and classic "xanthoma striata palmaris" was found in more than half. Twenty-seven percent had ischemic heart disease, detected earlier in men than in women. Twenty-seven percent had peripheral vascular disease (compared to 4% of subjects with type II hyperlipoproteinemia). Twenty-five of 35 subjects achieved normal lipid levels with dietary therapy alone. Analysis of 29 kindred showed hyperlipidemia in half of adult blood relatives; half of these had type III, the remainder usually had sample endogenous hyperglyceridemia (type IV). Only 2 of 55 children less than 20 years of age were affected, both with type IV.

Adult↗