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Biomedical subjects

W V Brown

Publications and source records attributed to W V Brown.

At least 91 records · Page 5Linked to original sources
PubMed1985

Plasma lipoprotein abnormalities associated with acquired hepatic triglyceride lipase deficiency.

Two enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are released into human plasma after intravenous injection of heparin. LPL is the major enzyme responsible for initiating catabolism of chylomicrons and very-low-density lipoproteins (VLDL). The physiological role of HTGL is less certain. HTGL has been postulated to be an alternate enzyme to LPL in hydrolysis of triglyceride in VLDL and to be an important enzyme for removal of phospholipid from both low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In this latter role, this enzyme would convert larger, lighter lipoprotein particles to smaller denser particles. HTGL deficiency has been found in severe liver disease and with a genetic deficiency of this enzyme. A unique patient is described with acquired hepatic triglyceride lipase deficiency and vitamin A intoxication. This patient developed hypercholesterolemia with an increase in both LDL and HDL. An increased proportion of lighter LDL (LDL1) and HDL (HDL2) was noted. In addition, after administration of heparin there was no shift in the distribution of apoE in plasma fractionated using a column containing 4% agarose. These findings are consistent with a postulated role of HTGL in metabolism of light LDL and HDL particles and some classes of apoE containing lipoproteins.

Chromatography, Agarose↗
PubMed1985

Coronary heart disease and the consumption of diets high in wheat and other grains.

Diets high in cereal grains, legumes and other vegetables are consistently associated with a reduced incidence of cardiovascular disease. This appears to be due primarily to the associated reduction in serum cholesterol and low density lipoprotein cholesterol. Replacement of animal fats and specifically the saturated fat and cholesterol components with complex carbohydrates and with unsaturated fat from vegetable sources appear to be the major reasons for the reduced levels of serum cholesterol. Additional effects of the high carbohydrate diets from vegetable sources may be caused by certain plant fibers including lignin, pectin and gums. Vegetable proteins may also have an intrinsic cholesterol reducing effect as compared to certain animal proteins, such as casein. A habitual increase in vegetable grains in the western diet should produce a sustained reduction in the risk of cardiovascular disease without a sacrifice of nutritional adequacy.

Adult↗
PubMed1985

Effect of heparin-induced lipolysis on the distribution of apolipoprotein e among lipoprotein subclasses. Studies with patients deficient in hepatic triglyceride lipase and lipoprotein lipase.

In normal subjects, apolipoprotein E (apo E) is present on very low density lipoproteins (VLDL) (fraction I) and on particles of a size intermediate between VLDL and low density lipoproteins (LDL) (fraction II). The major portion of apo E is, however, on particles smaller than LDL but larger than the average high density lipoproteins (HDL) (fraction III). To investigate the possible role of the vascular lipases in determining this distribution of apo E among the plasma lipoproteins, we studied subjects with primary deficiency of either hepatic lipase or of lipoprotein lipase and compared them with normal subjects. Subjects with familial hepatic triglyceride lipase deficiency (n = 2) differ markedly from normal in that fraction II is the dominant apo E-containing group of lipoproteins. When lipolysis of VLDL was enhanced in these subjects upon release of lipoprotein lipase by intravenous heparin, a shift of the apo E from VLDL into fractions II and III was observed. In contrast, apolipoproteins CII and CIII (apo CII and CIII, respectively) did not accumulate in intermediate-sized particles but were shifted markedly from triglyceride rich lipoproteins to HDL after treatment with heparin. In subjects with primary lipoprotein lipase deficiency (n = 4), apo E was confined to fractions I and III. Release of hepatic triglyceride lipase by heparin injection in these subjects produced a shift of apo E from fraction I to III with no significant increase in fraction II. This movement of apo E from large VLDL and chylomicron-sized particles occurred with little hydrolysis of triglyceride and no significant shift of apo CII or CIII into HDL from triglyceride rich lipoproteins. When both lipoprotein lipase and hepatic triglyceride lipase were released by intravenous heparin injection into normal subjects (n = 3), fraction I declined and the apo E content of fraction III increased by an equivalent amount. Either moderate or no change was noted in the intermediate sized particles (fraction II). These data strongly support the hypothesis that fraction II is the product of the action of lipoprotein lipase upon triglyceride rich lipoproteins and is highly dependent on hepatic triglyceride lipase for its further catabolism. In addition, the hydrolysis by hepatic triglyceride lipase of triglyceride rich lipoproteins in general results in a preferential loss of apo E and its transfer to a specific group of large HDL.

Adult↗
PubMed1985

Evidence for non-equilibrating pools of apolipoprotein C-III in plasma lipoproteins.

Using immunoaffinity chromatography to isolate apoC-III from radiolabeled lipoproteins for direct determination of specific radioactivity, we have studied the metabolism of human apoC-III in VLDL and in HDL following the bolus injection of 125I-labeled VLDL. Transfer of apoC-III radioactivity from VLDL to HDL was detected in the plasma sample drawn 5 min after injection of the tracer. However, the specific radioactivity of apoC-III in VLDL was found to be higher than that in HDL, with this difference being maintained throughout the sampling period (48-72 hr). The ratios of the respective specific activities ranged from 1.2 to 1.9 in six subjects studied (two normolipidemics and four hypertriglyceridemics). When 125I-labeled HDL was injected as the tracer, however, the higher apoC-III specific radioactivity was associated with the HDL fraction. This lack of complete equilibration of apoC-III between VLDL and HDL in vivo was further characterized by in vitro studies using either 125I-labeled VLDL or 125I-labeled HDL. All incubations were carried out for 3 hr at 37 degrees C followed by 16 hr at 4 degrees C and the apoC-III specific activity in each lipoprotein fraction was directly determined after immunoaffinity chromatography. In a study of plasma from a mildly hypertriglyceridemic subject in which 125I-labeled VLDL was incubated with unlabeled HDL, apoC-III specific activities in VLDL remained 30% greater than that in HDL. When 125I-labeled HDL (from the same subject) was incubated with unlabeled VLDL of apoC-III, final specific activity in VLDL was less than 10% of that of HDL apoC-III. Differences in specific activities were also demonstrated when radiolabeled purified apoC-III was exchanged onto VLDL prior to its incubation with HDL. A consistent difference in apoC-III specific activities in VLDL and HDL was observed after isolation of the particles either by molecular sieve chromatography or by ultracentrifugation. These studies demonstrated that, while the exchange of apoC-III between VLDL and HDL may be very rapid, this equilibration is not complete. Pools of apoC-III that do not participate in the equilibration process are present in both the VLDL and HDL fractions and could account for 30-60% of the total apoC-III mass in each lipoprotein fraction.

Adult↗
PubMed1984

Protocol for efficient plasma sampling for low density lipoprotein turnover studies.

Radiolabeled low density lipoprotein (LDL) is commonly used to study the turnover of LDL apolipoprotein B (apoB), the major protein component of LDL. Following an intravenous injection of radioiodinated LDL, typical sampling schedules have including 20-25 samples over a 14-day period with frequent sampling during the first 12 hr and daily samples thereafter. This is a burdensome task for subjects and investigators. To improve acceptance of the procedure, we have examined the effects of reduced sampling schedules upon the estimation of the fractional catabolic rate (FCR) for LDL apoB. Data from 36 different sets of LDL decay curves obtained from investigations of subjects with a variety of lipoprotein phenotypes have been used to test these schedules. Our results indicate that by choosing specific intervals over a 14-day period only 10 samples are sufficient to accurately determine the fractional catabolic rate for LDL in plasma. This reduced sampling schedule should facilitate the study of LDL turnover in large groups of subjects as outpatients.

Apolipoproteins B↗
PubMed1984

Diet and the decrease of coronary heart disease.

Total plasma cholesterol is a powerful predictor of death related to coronary heart disease (CHD). Strong evidence indicates that reducing the plasma cholesterol level results in in a decrease in the expected incidence of CHD. The decline in the death rate from CHD in the U.S. population over the past 2 decades has occurred simultaneously with a reduction in the consumption of cholesterol and saturated fat and a dramatic increase in the use of unsaturated vegetable oils. Over the same period, the mean cholesterol level has decreased at least 5%. This finding explains up to one-third of the decline in CHD mortality observed since 1968.

Adult↗
PubMed1984

Elevated hemoglobin A1c and low-density lipoprotein cholesterol levels in thiazide-treated diabetic patients.

Despite the well-known hyperglycemic effect of thiazide diuretics, these agents are often administered to diabetic patients. This study compared 89 insulin-treated diabetic patients receiving hydrochlorothiazide, 57 receiving furosemide, and 255 receiving no diuretic. Hemoglobin A1c level was 7.2 +/- 1.8 percent (mean +/- SD) with hydrochlorothiazide, significantly higher than the levels of 5.9 +/- 2.3 percent with furosemide and 6.4 +/- 2.0 percent with no diuretic. Low-density lipoprotein cholesterol level was 154 +/- 43 mg/dl with hydrochlorothiazide, but 134 +/- 42 mg/dl with furosemide and 130 +/- 42 mg/dl with no diuretic. Multivariate analysis showed that the associations remained significant after adjustment for age, sex, race, type and duration of diabetes, body mass index, blood pressure, serum potassium level, insulin dose, and treatment with other medications. These findings suggest that treatment with thiazide diuretics in the diabetic population may increase low-density lipoprotein cholesterol and hemoglobin A1c levels.

Cholesterol↗
PubMed1984

Precipitation of apo E-containing lipoproteins by precipitation reagents for apolipoprotein B.

We measured the solubility of apolipoprotein E (apo E) after precipitation, with heparin-Mn2+ or dextran sulfate-Mg2+, of lipoproteins containing apo B. Data from 46 randomly selected subjects suggest that apo E is readily precipitated by dextran sulfate-Mg2+, but that heparin-Mn2+ preferentially precipitates apo E associated with apo B-containing lipoproteins while leaving the apo E-containing fraction of high-density lipoproteins (HDL) in solution. In a more detailed analysis of three subjects, we measured the lipoprotein association of apo E by column chromatography on agarose beads, before and after its precipitation from plasma. This study confirmed the preferential solubility of apo E associated with HDL lipoproteins. Using plasma from two normolipidemic subjects, we maintained the heparin concentration at 1.30 g/L and varied the manganese concentration from 9.2 to 184 mmol/L. A 46 mmol/L concentration best separated apo E-containing HDL from apo B-containing lipoproteins. Thus, at these final concentrations, heparin-Mn2+ appears to precipitate the apo E associated with apo B-containing lipoproteins, leaving soluble most of the apo E associated with lipoproteins of HDL size.

Apolipoprotein A-I↗
PubMed1983

Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse.

Two triglyceride lipases, lipoprotein lipase and hepatic triglyceride lipase, participate in the metabolism of plasma lipoproteins. A single recessive mutation, cld, on mouse chromosome 17 causes an apparent deficiency of both lipoprotein lipase and hepatic triglyceride lipase activities. Mice homozygous for this defect develop lethal hyperchylomicronemia within 2 days postpartum as a consequence of nursing. Plasma triglyceride values in affected mice often reach 20,000 milligrams per deciliter (100 times higher than that in normal littermates), and total lipase activity in plasma or tissues is 5 to 20 percent of that in controls.

Animals↗
PubMed1983

Measurement of lipoprotein lipase and hepatic triacylglycerol lipase in post-heparin plasma of the cynomolgus monkey.

Conditions for measurement of the lipolytic activities, lipoprotein lipase and hepatic triacylglycerol lipase in cynomolgus monkey postheparin plasma are described. The two activities are separable by heparin-Sepharose chromatography. Goat anti-human hepatic triacylglycerol lipase serum inhibits monkey hepatic triacylglycerol lipase activity and allows direct measurement of lipoprotein lipase in post-heparin plasma. While both human and homologous serum can be used as a source of activator apolipoprotein, homologous serum produces a much greater activation.

Animals↗
PubMed1983

Metabolism of apoprotein B in cynomolgus monkey: evidence for independent production of low-density lipoprotein apoprotein B.

The catabolism of very-low-density lipoprotein apoprotein B and its conversion to low-density lipoprotein was studied in five chow-fed cynomolgus monkeys following injection of radioiodinated homologous very-low-density lipoproteins. The mean (+/- SD) fractional catabolic rate of very-low-density lipoprotein apoprotein B was 0.97 +/- 0.20 h-1 and the mean (+/- SD) production rate was 0.76 +/- 0.20 mg X kg-1 X h-1. The percent of conversion of very-low-density lipoprotein apoprotein B to low-density lipoprotein ranged from 33 to 59%. In separate studies of low-density lipoprotein apoprotein B turnover performed using homologous radiolabeled low-density lipoprotein in five additional animals, the mean (+/- SD) fractional catabolic rate for low-density lipoprotein apoprotein B was 0.050 +/- 0.017 h-1 and the mean (+/- SD) apoprotein B production rate was 0.70 +/- 0.18 mg X kg-1 X h-1. Comparison of the total low-density lipoprotein apoprotein B production with that derived from very-low-density lipoprotein apoprotein B suggested that a large fraction of plasma low-density lipoprotein apoprotein B was derived from a source exclusive of circulating very-low-density lipoprotein apoprotein B. This was confirmed in two animals by simultaneous injection of radiolabeled very-low-density and low-density lipoproteins. Thus, a significant proportion of cynomolgus monkey low-density lipoproteins are produced either by direct hepatic secretion or by rapid conversion of lower-density lipoproteins before they appear in the peripheral circulation.

Animals↗
PubMed1983

Apolipoprotein E-enriched lipoprotein subclasses in normolipidemic subjects.

This study was undertaken to objectively define the lipoprotein association of apoE without ultracentrifugation and represents a description of three distinct apoE-containing lipoprotein (LP) subclasses in normal human plasma. The lipoproteins of whole plasma were fractionated in a continuous manner by molecular sieve chromatography using 4% agarose and the elution profile of apoE was compared to that of apoB, apoA-I, cholesterol, and triglyceride. The data show that all apoE in normal subjects is LP-associated and is confined to three discrete LP subfractions of characteristic size. The largest (fraction I), appears to be a subclass of very low density lipoproteins (VLDL). The other two, however, are distinct in size from the major cholesterol-carrying LP; fraction II is intermediate in size between VLDL and the major apoB-containing lipoprotein, LDL; and fraction III is larger than the major apoA-I-containing lipoproteins, HDL, but smaller than LDL. Parallel chromatography of supernatant and infranatant fractions obtained after ultracentrifugation of serum at each of three different densities, 1.006, 1.019, and 1.063 g/ml confirmed that fraction I is of density less than 1.006 g/ml, but that fractions II and III overlap the conventional density intervals.

Apolipoproteins↗
PubMed1983

Direct measurement of apoprotein C-III specific activity in 125I-labeled very low density lipoproteins using immunoaffinity chromatography.

We have developed a technique for isolating apoprotein C-III by immunoaffinity chromatography, allowing the measurement of its specific radioactivity in lipoprotein fractions from small plasma samples. IgG specific for apoC-III was purified from goat antisera and bound to Sepharose. One ml of this gel (5 mg of IgG) bound 80-90 micrograms of apoC-III. The specific activity of apoC-III was determined by application of delipidated very low density lipoproteins to 1-ml columns and analysis of the protein eluted at pH 2.5 for mass and radio-activity. The coefficient fo variation for apoC-III specific activity determination from 125I-labeled VLDL was 4.3%. Minimal contamination of the eluates by apoproteins B, E, and C-II was confirmed by radioimmunoassay (0.3-1.2%). Following the injection of autologous 125I-labeled VLDL, specific activity decay curves for VLDL apoC-III were biexponential, with the clearance of apoC-III being slower in hypertriglyceridemic subjects. These affinity columns can be used repeatedly and yield reproducible results. This technique should be useful for simultaneous studies of the turnover of several apoproteins in the same individual following a single injection of labeled autologous lipoprotein.

Apolipoprotein C-III↗
PubMed1982

Lipoprotein metabolism during acute inhibition of hepatic triglyceride lipase in the cynomolgus monkey.

The role of the enzyme hepatic triglyceride lipase was investigated in a primate model, the cynomolgus monkey. Antisera produced against human postheparin hepatic lipase fully inhibited cynomolgus monkey posttheparin plasma hepatic triglyceride lipase activity. Lipoprotein lipase activity was not inhibited by this antisera. Hepatic triglyceride lipase activity in liver biopsies was decreased by 65-90% after intravenous infusion of this antisera into the cynomolgus monkey. After a 3-h infusion of the antisera, analytic ultracentrifugation revealed an increase in mass of very low density lipoproteins (S(f) 20-400). Very low density lipoprotein triglyceride isolated by isopycnic ultracentrifugation increased by 60-300%. Analytic ultracentrifugation revealed an increase in mass of lipoproteins with flotation greater than S(f) 9 (n = 4). The total mass of intermediate density lipoproteins (S(f) 12-20) approximately doubled during the 3 h of in vivo enzyme inhibition. While more rapidly floating low density lipoproteins (S(f) 9-12) increased, the total mass of low density lipoproteins decreased after infusion of the antibodies. The changes in high density lipoproteins did not differ from those in control experiments. In order to determine whether the increases of plasma concentrations of very low density lipoproteins were due to an increase in the rate of synthesis or a decrease in the rate of clearance of these particles, the metabolism of radiolabeled homologous very low density lipoproteins was studied during intravenous infusion of immunoglobulin G prepared from the antisera against hepatic triglyceride lipase (n = 3) or preimmune goat sera (n = 3). Studies performed in the same animals during saline infusion were used as controls for each immunoglobulin infusion. There was a twofold increase in the apparent half-life of the very low density lipoprotein apolipoprotein-B tracer in animals receiving the antibody, consistent with a decreased catabolism of very low density lipoproteins. Concomitantly, the rise in low density lipoprotein apoprotein-B specific activity was markedly delayed. None of these changes were observed during infusion of preimmune immunoglobulin G.Hepatic triglyceride lipase participates with lipoprotein lipase in the hydrolysis of the lipid in very low density lipoproteins, intermediate density lipoproteins, and the larger low density lipoproteins (S(f) 9-12). Thus, hepatic triglyceride lipase appears to function in a parallel role with lipoprotein lipase in the conversion of very low density and intermediate density lipoproteins to low density lipoproteins (S(f) 0-9).

Animals↗