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Biomedical subjects

D B Zilversmit

Publications and source records attributed to D B Zilversmit.

At least 19 recordsLinked to original sources
PubMed1995

Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins.

In addition to low-density lipoproteins, plasma chylomicrons and very-low-density lipoproteins (VLDL) contribute to atherogenesis. When triglyceride-rich particles bind to arterial endothelium and to deendothelialized areas, locally present lipoprotein lipase initiates triglyceride hydrolysis and decreases the size of the adhering particles. Additional changes in composition are brought about by the exchange of lipids between chylomicron/VLDL remnants and the cholesteryl ester-rich low- and high-density lipoproteins. These exchanges are mediated by lipid transfer proteins in plasma. Animal studies with doubly labeled lipoproteins show that the size of lipoprotein particles determines their rate of entering the artery and contributes to the formation of lesions. This model supports epidemiologic studies that have identified plasma triglycerides as a risk factor for atherogenesis. The model for a causal role of pre- and postprandial triglyceride-rich lipoproteins in atherogenesis suggests that measuring them may improve the assessment of cardiovascular risk factors.

Adult↗
PubMed1991

Effects of hyperlipidemias in hamsters on lipid transfer protein activity and unidirectional cholesteryl ester transfer in plasma.

Experiments were performed to characterize plasma lipid transfer protein activity (LTA), and the rate of [3H]CE transfer from HDL to lower density lipoproteins in plasma of hamsters. Compared to rabbits, hamster plasma has about one-tenth the level of d greater than 1.21 LTA but a relatively high level of VLDL-triacylglycerols, and a higher fractional rate of HDL-[3H]CE transfer in plasma (in vitro) than predicted by the d greater than 1.21 LTA. Like the rat, hamster plasma contains an inhibitor(s) of LTA; the level of the inhibitor activity in d greater than 1.21 g/ml plasma was similar in normal and hyperlipoproteinemic hamsters. Hypertriglyceridemia in sucrose-fed hamsters did not affect LTA, cholesteryl ester transfer or the plasma level of HDL-CE. However, a comparable degree of hypercholesterolemia was associated with a 122% increase in plasma d greater than 1.21 LTA and a 63% increase in the fractional rate of [3H]CE transfer from HDL to lower density lipoproteins in plasma. Cholesterol feeding in hamsters was associated with increased plasma levels of LDL-cholesterol and, to a lesser extent, with VLDL- and IDL-cholesterol.

Animals↗
PubMed1989

Impaired triacylglycerol catabolism in hypertriglyceridemia of the diabetic, cholesterol-fed rabbit: a possible mechanism for protection from atherosclerosis.

The etiology of the hypertriglyceridemia in alloxan-diabetic rabbits was studied by two independent methods. Production and removal rates of VLDL triacylglycerol were measured in diabetic rabbits by injection of [3H]palmitate-labelled VLDL. Similarly, triacylglycerol total removal rates were determined in non-diabetic rabbits which were infused with Intralipid to mimic the plasma triacylglycerol concentrations of diabetic rabbits. Compared to nondiabetic rabbits, triacylglycerol removal rats were decreased in diabetic rabbits, particularly at higher levels of plasma triacylglycerol. During cholesterol and triacylglycerol supplementation of the diet, post-heparin plasma lipoprotein lipase activity of diabetic rabbits with severe hypertriglyceridemia averaged 36% of that of nondiabetics, suggesting an impaired triacylglycerol removal capacity. Furthermore, plasma triacylglycerol was inversely related to post-heparin plasma lipoprotein lipase activity among diabetic rabbits. VLDL triacylglycerol production increased with increasing plasma triacylglycerol concentration among diabetic cholesterol-fed rabbits with moderately severe hypertriglyceridemia, but reached an apparent plateau among rabbits with plasma triacylglycerol concentrations from approx. 2000-9000 mg/dl. Thus, severe hypertriglyceridemia in this model of insulin deficiency can be attributed only partially to VLDL hypersecretion, whereas a removal defect, resulting in saturation of the triacylglycerol removal mechanism, appears to be largely responsible. The impaired removal of plasma triacylglycerol is also related to the presence of cholesterol predominantly in lipoproteins of increased size. The data support the hypothesis that protection against atherosclerosis in cholesterol-fed diabetic rabbits results from exclusion of very large cholesterol-containing lipoproteins from the arterial wall.

Animals↗
PubMed1989

The arterial barrier to lipoprotein influx in the hypercholesterolemic rabbit. 1. Studies during the first two days after mild aortic injury.

These studies examine the hypothesis that removal of aortic endothelium eliminates a barrier to lipoprotein cholesterol influx. The aortas of rabbits fed a cholesterol-rich diet from 7 to 16 days before balloon injury were studied 1 or 2 days after deendothelialization of specific areas of the aorta. By this design the aortic sterol content was near normal on the day of injury, but areas of injured and noninjured aorta were exposed to identical levels of elevated plasma cholesterol. Measuring the arterial [3H]- and [14C] cholesterol fractions accumulated during 2 different intervals after dosage in the same animals permitted calculation of total influx and fractional loss of aortic cholesterol. During the first 2 days after deendothelialization, total (unidirectional) cholesteryl ester influx in deendothelialized aorta was similar to that in adjacent uninjured aorta, but total influx of nonesterified cholesterol was increased. The calculated increase in influx of nonesterified cholesterol was not a result of an increase in hydrolysis of entered cholesteryl ester but probably represents increased exchange of labeled cholesterol between artery and plasma. These results suggest that subendothelial layers of the aorta of short-term cholesterol-fed rabbits function as significant barriers to lipoprotein influx and that processes other than increased permeation by lipoproteins initiate injury-induced lesions.

Albumins↗
PubMed1989

The arterial barrier to lipoprotein influx in the hypercholesterolemic rabbit. 2. Long-term studies in deendothelialized and reendothelialized aortas.

These studies consider whether a mild aortic injury that does not increase cholesteryl ester influx during the first few days promotes atheromatosis in the hypercholesterolemic rabbit. The cholesteryl ester influx in uninjured, deendothelialized, and reendothelialized aorta was also measured in order to account for the different cholesteryl ester contents in these areas. By 32-33 days after localized aortic injury which was made after 5-7 days of cholesterol feeding, uninjured (control) areas of the thoracic aortas had accumulated 48 micrograms/cm2 each of esterified and nonesterified cholesterol due to continued cholesterol feeding. However, the previously injured deendothelialized and reendothelialized areas of the aortas had accumulated 6 and 10 times as much esterified cholesterol, and 2 and 5 times as much nonesterified cholesterol, respectively, as the adjacent uninjured areas. Esterified cholesterol influx was low during the second day after injury but increased with time so that 30-31 days later the esterified cholesterol influx in deendothelialized and reendothelialized aorta was respectively 44 and 7 times as great as the 0.1 microgram/h/cm2 in the adjacent uninjured aorta. However, expressed per mg aortic cholesteryl ester, cholesteryl ester influx in reendothelialized aorta was no greater than in noninjured aorta. These studies suggest that an injury that does not initially increase cholesteryl ester influx can promote atheromatosis and that the higher rate of cholesteryl ester influx that develops with time in reendothelialized areas is closely related to its increased cholesteryl ester content.

Albumins↗
PubMed1989

High density lipoprotein metabolism in a rabbit model of hyperalphalipoproteinemia.

The potential utility of an animal model of hyperalphalipoproteinemia for examining the role of high density lipoprotein (HDL) in atherogenesis prompted the current studies. Preliminary data indicated that in rabbits high-coconut oil feeding for 30 days doubled plasma HDL-cholesterol levels, but did not affect lower density lipoproteins (LDL) (d less than 1.063 g/ml). Experiments were performed to examine the composition of these HDL and to determine the mechanism for the diet-induced increase in plasma HDL. Rabbits were fed commercial chow or chow plus 14% (w/w) coconut oil and blood samples were collected 18 h after feeding. Compared to chow-fed rabbits, peak levels of HDL-cholesterol were attained within 2 weeks, and coconut oil feeding doubled the plasma levels of HDL-cholesterol, phospholipids and protein for up to 4 months without affecting HDL lipid and apoprotein composition. After 3 months the diet also increased VLDL- (107%) and LDL-cholesterol (40%) levels, but the absolute increases in each of these lipoprotein fractions was less than half of that of HDL. Isotope kinetic studies of 125I-HDL protein indicated a doubled rate of production of HDL and no change in the efficiency of removal of HDL from plasma. These studies demonstrate that in the rabbit high-coconut oil feeding doubles the rate of production and turnover of apparently normal HDL particles. It is proposed that such an animal model could be utilized to examine directly the role of HDL in atherogenesis.

Animals↗
PubMed1989

Quantitation of apoB-48 and apoB-100 by gel scanning or radio-iodination.

In this presentation, we have validated two procedures for the separation and quantitation of apoB-48 and apoB-100 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE): 1) gamma counting of radio-iodinated lipoproteins and 2) scanning of stained gels. Total apoB in SDS solutions was determined by absorbance at 220 nm, and validated by amino acid analysis. The absorbance at 220 nm, in contrast to the Lowry procedure, could be used with BSA as a standard without correction factors. At relative apoB-48 concentrations higher than 10% of total apoB, both scanning and radio-iodination gave reliable results. At lower relative apoB-48 concentrations, the radio-iodine method appeared to be superior, but at low total apoB concentrations, the efficiency of radio-iodination was low.

Amino Acids↗
PubMed1989

A novel explanation for the reduced LDL cholesterol in severe hypertriglyceridemia.

When [3H]cholesteryl ester-labeled low density (LDL) and intermediate density lipoproteins (IDL) from a normotriglyceridemic, hypercholesterolemic rabbit were injected into severely hypertriglyceridemic, hypercholesterolemic rabbits, 60% of the label appeared in very low density lipoproteins (VLDL) at 3 hr. A similar experiment showed that 40% of injected 131I-protein-labeled LDL appeared in the IDL fraction at 4 hr. Taken together, these data suggest that the exchange of LDL cholesteryl ester for VLDL triglyceride results in a density shift of injected LDL to the IDL density range. Furthermore, the percent of injected 131I-labeled LDL from normotriglyceridemic rabbits that appeared in the IDL fraction increased in rabbits with increasing levels of plasma triglyceride. This LDL density shift was reproduced in vitro by incubating iodinated LDL from normotriglyceridemic, hypercholesterolemic rabbits with concentrations of VLDL from hypertriglyceridemic, hypercholesterolemic rabbits similar to those in plasma. With such a system, it was shown that the percentage of LDL that appeared in the IDL fraction increased with time, was enhanced fourfold by the addition of plasma lipid transfer protein, increased with increasing molar ratio of triglyceride to cholesteryl ester in VLDL, but apparently did not increase with increasing VLDL particle number. These studies suggest that a pronounced decrease in density of lipoproteins that would normally appear in the LDL density range, resulting from loss of cholesteryl ester in exchange for VLDL triglyceride, may explain, at least in part, the reduced LDL levels in severe hypertriglyceridemia.

Animals↗
PubMed1988

Hyperglycemia in normotriglyceridemic, hypercholesterolemic insulin-treated diabetic rabbits does not accelerate atherogenesis.

Severely hyperlipidemic alloxan-diabetic cholesterol-fed rabbits were treated with different daily doses of insulin in order to study the effect of insulin on plasma lipids, lipoproteins and postheparin lipoprotein lipase activity. At plasma triglyceride levels of 15,000 mg/dl, untreated diabetic rabbits carried 73% (1950 mg/dl) of plasma total cholesterol in lipoproteins with a diameter larger than 75 nm (Sf greater than 400), 25% in smaller very low density lipoproteins (VLDL) and 1% in both low and high density lipoproteins (LDL, HDL). Insulin treatment greatly reduced plasma total cholesterol and triglyceride concentrations. The decrease of plasma total cholesterol concentration was paralleled by a decrease in the cholesterol of the largest lipoproteins (Sf greater than 400) and an increase in cholesterol of both smaller very low density lipoproteins and low density lipoproteins. At the same time, postheparin plasma lipoprotein lipase activity increased 2-8-fold. When plasma triglyceride levels were normalized by insulin treatment, the lipoprotein cholesterol distribution in diabetic cholesterol-fed rabbits was similar to that of normal cholesterol-fed rabbits. To study development of atherosclerosis, diabetic rabbits were cholesterol-fed and treated with insulin for eight weeks such that the triglyceride levels were normalized, but plasma glucose levels were still greatly elevated. Nondiabetic rabbits were cholesterol-fed simultaneously. Plasma cholesterol and triglyceride levels were similar in the two groups of rabbits, as well as cholesterol in Sf greater than 400 or smaller VLDL and cholesterol in HDL. However, LDL-cholesterol concentration in the insulin-treated diabetic rabbits was 1.5-2 times that in the nondiabetic rabbits. The two groups of rabbits developed similar degrees of atherosclerosis, as judged by aortic cholesterol content. Apparently, partially controlled diabetes in cholesterol-fed rabbits does not accelerate atherogenesis beyond that observed in nondiabetic cholesterol-fed rabbits.

Animals↗
PubMed1988

Evidence for an inverse relation between plasma triglyceride and aortic cholesterol in the coconut oil/cholesterol-fed rabbit.

Rabbits fed a commercial chow diet containing 0.5% cholesterol and 14% coconut oil developed more severe hyperlipidemia and atherosclerosis than rabbits fed the same diet containing olive oil in place of coconut oil. Average plasma cholesterol was twice as high in the coconut oil/cholesterol-fed rabbits than in olive oil/cholesterol-fed rabbits. Final plasma triglycerides, although highly variable, were approx. 20-fold higher than basal plasma triglyceride in coconut oil/cholesterol-fed rabbits; plasma triglyceride in olive oil/cholesterol-fed rabbits remained unchanged throughout the study period. In coconut oil/cholesterol-fed rabbits, a direct relationship between plasma triglyceride and aortic cholesterol was not found. Plasma cholesterol and aortic cholesterol were also not correlated at a statistically significant level (r = 0.26, P greater than 0.25). However, when both plasma cholesterol and triglyceride were simultaneously introduced as predictors of aortic cholesterol, the correlation between these plasma lipids and aortic cholesterol became highly significant (r = 0.64, P less than 0.02). Aortic cholesterol increased in proportion to plasma cholesterol concentrations but appeared to be inversely related to plasma triglyceride levels.

Animals↗
PubMed1988

Plasma lipid transfer activity in rabbits: effects of dietary hyperlipidemias.

Studies were performed in the rabbit to investigate the relationship between plasma lipids and the cholesteryl ester/triglyceride transfer activity of lipoprotein-deficient plasma (d greater than 1.21). The time courses for diet-induced changes in plasma lipids and the lipid (cholesteryl ester/triglyceride) transfer activity of lipoprotein-deficient plasma (LTA) were determined in rabbits fed a variety of hyperlipidemic diets. LTA was not altered within 36 h after a single high-cholesterol/oil meal despite a near doubling of the concentration of plasma cholesterol. With high cholesterol and/or high-fat feeding, LTA increased and reached new steady state levels within about 10 days with little additional change for up to 87 days even when plasma cholesterol continued to increase. For all diets, the greatest increments in LTA occurred about 5 days after initiation of experimental feeding. A low-cholesterol (0.05-0.2%, w/w) diet and a cholesterol-free, high-coconut oil diet (14%, w/w) were associated with comparable increases in both plasma cholesterol and LTA. A marked, concomitant increase in plasma triglycerides was not associated with a further increase in LTA in hypercholesterolemic rabbits. These data indicate that in the rabbit LTA increases in a parabolic manner with moderate and gross, diet-induced increases in plasma cholesterol, and the time courses for the diet-induced changes in LTA are similar for a variety of hyperlipidemic diets.

Animals↗
PubMed1988

Dissociation between cholesterol secretion and plasma lipid transfer activity in rabbits.

Human and rabbit plasma contains a lipid transfer protein that transfers cholesteryl esters and triglycerides among the plasma lipoproteins and may also have a role in the movement of lipids into and out of cells. Little is known about the regulation of the activity of the lipid transfer protein, but in the rabbit, hypercholesterolemia is associated with increased plasma lipid transfer activity (LTA). Perfused rabbit livers secrete LTA, and hepatic cholesterol secretion is increased in rabbits with diet-induced hypercholesterolemia. Thus, experiments were performed with rabbits to determine if LTA is regulated by a concerted hepatic secretion of lipoprotein protein cholesterol and LTA. Rabbits were fed chow or chow plus coconut oil (14% wt/wt), and plasma lipids, LTA, and the rate of secretion of cholesterol into plasma were determined. Coconut oil feeding increased plasma cholesterol by 68%, LTA by 42%, and hepatic cholesterol secretion by 69%. Mevinolin (75 mg/day), an inhibitor of cholesterol biosynthesis, lowered LTA and plasma cholesterol without affecting the rate of secretion of cholesterol into plasma. These studies provide further evidence that, in the rabbit, plasma cholesterol and LTA are closely related, and the association is not likely to be caused by a concerted hepatic secretion of cholesterol and LTA.

Animals↗
PubMed1988

Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits.

In diabetic hypercholesterolemic rabbits at plasma triglyceride concentrations of approximately 5000 mg/dl, 55% of plasma cholesterol (1400 mg/dl) was in lipoproteins with diameters larger than 75 nm (Sf greater than 400), 40% in smaller very low density and intermediate density lipoproteins, 4% in low density lipoproteins, and 1% in high density lipoproteins. Specific intimal clearance (nl/h.mg aortic cholesterol) of the giant Sf greater than 400 lipoproteins was about 4% of that of the low density lipoproteins. The data suggest that even very low density lipoproteins with diameters smaller than 75 nm were practically excluded from entering the arterial wall. Specific intimal clearance of low density lipoproteins in hypertriglyceridemic, diabetic cholesterol-fed rabbits was similar to that in normal cholesterol-fed rabbits, but low density lipoprotein concentrations in diabetic rabbits were low. Thus, at plasma triglyceride concentrations of approximately 5000 mg/dl, only 5% of plasma cholesterol may be readily available for infiltration of arteries. These results add further support to the hypothesis that hypertriglyceridemic, diabetic cholesterol-fed rabbits are protected against atherogenesis because the major part of plasma cholesterol is carried in large lipoproteins to which the artery is not very permeable.

Animals↗
PubMed1987

Blockade of intestinal lipoprotein clearance in rabbits injected with Triton WR 1339-ethyl oleate.

Although Triton WR 1339 has been used to block triglyceride or cholesterol removal from plasma, no data are available on the extent to which Triton WR 1339 administered to rabbits blocks clearance of newly absorbed dietary lipids. In the present study, we have measured the efficiency of this blockade during a 24-hr interval. After the Triton WR 1339 administration, plasma Sf greater than 400 and d less than 1.019 g/ml lipoprotein lipid concentrations increased greatly, but the concentration of d greater than 1.019 g/ml lipids decreased. In the rabbits fed 0.5% cholesterol for 1 week, the increase in d less than 1.019 g/ml and the decrease in 1.019 less than d less than 1.063 g/ml lipoprotein fractions 24 hr after the Triton WR 1339 injection were much greater than in the chow-fed Tritonized rabbits. After the Triton treatment, 50% of intravenously injected LDL-125I-labeled apoB disappeared in 24 hr, but little or no apoB appeared in other lipoprotein fractions and no VLDL apoB was converted to LDL. Labeled cholesterol and retinol were fed to rabbits and 24-hr increments in plasma cholesteryl- and retinyl-ester label and mass were measured. In chow-fed Tritonized rabbits about one-half of the absorbed oral doses of both labeled lipids was recovered in plasma, indicating that Triton WR 1339 does not completely inhibit the clearance of intestinal lipoproteins. When rabbits were injected with Triton and an ethyl oleate emulsion, the blockade of dietary lipid removal from plasma was substantially improved and chylomicron cholesterol uptake by extra-hepatic tissues was completely abolished.

Animals↗
PubMed1986

Disappearance and effects of exogenous lipid transfer activity in rats.

These studies were performed to determine the role of plasma lipid transfer activity in the regulation of plasma total and lipoprotein cholesterol in vivo. Partially purified human lipid transfer activity was injected into rats at a level similar to that of normal rabbit plasma, d greater than 1.21. The disappearance of exogenous lipid transfer activity from rat plasma was biphasic, with a 70% loss within 6 h. The remaining 30% was lost with a half-time of about 14 h. In the rat, short-term exposure (6 h) to high levels of lipid transfer activity resulted in a net transfer of cholesteryl esters from high density to d less than 1.019 lipoproteins, without affecting plasma total cholesterol. However, the lipid transfer activity-induced changes in lipoprotein cholesterol were not evident after 24 h, despite the fact that the lipid transfer activity of rat plasma d greater than 1.21 was similar to that of human plasma d greater than 1.21 during the preceding 18 h.

Animals↗
PubMed1986

Localization of intracellular triacylglycerol and cholesteryl ester transfer activity in rat tissues.

A triacylglycerol and cholesteryl ester transfer activity has been isolated from rat liver. After homogenization, the liver cells were subfractionated into the 10 000 X g pellet, microsomal fraction and postmicrosomal supernatant. Most of the transfer activity appeared to be associated with the microsomal fraction. Rough and smooth microsomes contained nearly equal transfer activities. When isolated microsomes were subject to proteolytic attack, the transfer activity was not inactivated, unless it had been released from the microsomes prior to proteolytic treatment. This indicates that the activity is probably located within the microsomal vesicles. Similar transfer activities were found in the intestinal mucosa of rats, whereas little or no activity was detected in the brain, heart, kidney, or plasma.

Animals↗