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Biomedical subjects

E L Bierman

Publications and source records attributed to E L Bierman.

At least 73 records · Page 4Linked to original sources
PubMed1983

Effect of positively charged sphingomyelin liposomes on cholesterol metabolism of cells in culture.

When cultured human skin fibroblasts were incubated at 37 degrees C with sonically dispersed positively charged sphingomyelin liposomes, sphingomyelin accumulated within the cell. This resulted in stimulation of cholesterol synthesis by increasing 3-hydroxy-3-methylglutaryl Coenzyme A reductase activity. Activation was rapid and was not due to the efflux of cell cholesterol or to cell growth and proliferation. Neither low density lipoprotein cholesterol nor nonlipoprotein cholesterol could suppress the sphingomyelin-induced cholesterol synthesis or activate the acyl-CoA cholesterol acyltransferase, despite an increase in cell cholesterol content. In contrast, the response to 7-ketocholesterol or 26-hydroxycholesterol was not impaired. The effect of sphingomyelin on cholesterol synthesis was temporary and reversible. Twenty-four hours after removal of sphingomyelin, cholesterol synthesis returned to normal and could be suppressed by LDL. Accumulation of sphingomyelin in the cell decreased lysosomal cholesteryl ester hydrolase but had no effect on the microsomal cholesteryl ester hydrolase. These results suggest that accumulation of sphingomyelin in the cell markedly affects cellular cholesterol homeostasis. Resultant accumulation of cholesteryl esters in the presence of extracellular cholesterol could be relevant to atherogenesis.

Cells, Cultured↗
PubMed1983

Reduced thermic effect of feeding in obesity: role of norepinephrine.

Several studies have suggested that obese subjects have a reduced thermic effect of feeding when compared to normal weight controls. The present study was undertaken to further define this apparent abnormality, and evaluate the role of norepinephrine in the thermic response to food. A test formula meal of 800 calories (85% carbohydrate, 15% protein) was taken by 7 control and 6 moderately obese subjects whose obesity was adult in onset. The rise in resting oxygen consumption following the test meal was greater in the control than in the obese group (p less than 0.01), and there was a significant inverse correlation between the relative degree of obesity and this response to feeding (r = -0.59, p less than 0.05). Norepinephrine concentrations were greater in the obese than in the control group both before (p less than 0.05) and after (p less than 0.05) feeding. No correlations were found between the plasma norepinephrine concentrations and the rise in oxygen consumption after feeding. Four of the 6 obese subjects were restudied after weight reduction. The reduced-obese group showed a trend toward normalization of basal measurements and responses to feeding. It is concluded that the reduced thermic response to feeding seen in the obese subjects studied cannot be directly accounted for by diminished sympathetic nervous system activity as reflected by plasma levels of norepinephrine.

Adult↗
PubMed1983

Hydrocortisone decreases the internalization of low density lipoprotein in cultured human fibroblasts and arterial smooth muscle cells.

The effect of hydrocortisone on the cellular low density lipoprotein (LDL) pathway was studied in cultured human skin fibroblasts and arterial smooth muscle cells. Hydrocortisone decreased both uptake and degradation of 125I-LDL, LDL binding, measured at 4 C, was not affected by the hormone. Physiological concentrations of hydrocortisone (4 . 1 X 10(-8) mol/l) resulted in a 30% reduction of LDL uptake and degradation which could not be accounted for by an effect of the hormone on macromolecular synthesis, cell protein or cell number. To test whether the decrease in uptake and degradation of 125I-LDL was due to reduced internalization, the effect of hydrocortisone on the internalization of prebound LDL was determined and found to be decreased. Also, preincubation with unlabelled LDL in the presence of hydrocortisone resulted in less down regulation of LDL receptor activity than when no hydrocortisone was present. An effect of the hormone on bulk phase endocytosis has been excluded, since hydrocortisone did not affect either LDL degradation by receptor negative cells or endocytosis of 14C-sucrose by normal skin fibroblasts. Thus, hydrocortisone impairs LDL catabolism by decreasing the internalization of LDL normally bound to its cell surface receptor. These results may be relevant to the pathogenesis of atherosclerosis in conditions associated with reduced cellular LDL catabolism.

Aorta, Thoracic↗
PubMed1983

Specific high-affinity binding of high density lipoproteins to cultured human skin fibroblasts and arterial smooth muscle cells.

Binding of human high density lipoproteins (HDL, d = 1.063-1.21) to cultured human fibroblasts and human arterial smooth muscle cells was studied using HDL subjected to heparin-agarose affinity chromatography to remove apoprotein (apo) E and B. Saturation curves for binding of apo E-free 125I-HDL showed at least two components: low-affinity nonsaturable binding and high-affinity binding that saturated at approximately 20 micrograms HDL protein/ml. Scatchard analysis of high-affinity binding of apo E-free 125I-HDL to normal fibroblasts yielded plots that were significantly linear, indicative of a single class of binding sites. Saturation curves for binding of both 125I-HDL3 (d = 1.125-1.21) and apo E-free 125I-HDL to low density lipoprotein (LDL) receptor-negative fibroblasts also showed high-affinity binding that yielded linear Scatchard plots. On a total protein basis, HDL2 (d = 1.063-1.10), HDL3 and very high density lipoproteins (VHDL, d = 1.21-1.25) competed as effectively as apo E-free HDL for binding of apo E-free 125I-HDL to normal fibroblasts. Also, HDL2, HDL3, and VHDL competed similarly for binding of 125I-HDL3 to LDL receptor-negative fibroblasts. In contrast, LDL was a weak competitor for HDL binding. These results indicate that both human fibroblasts and arterial smooth muscle cells possess specific high affinity HDL binding sites. As indicated by enhanced LDL binding and degradation and increased sterol synthesis, apo E-free HDL3 promoted cholesterol efflux from fibroblasts. These effects also saturated at HDL3 concentrations of 20 micrograms/ml, suggesting that promotion of cholesterol efflux by HDL is mediated by binding to the high-affinity cell surface sites.

Apolipoproteins↗
PubMed1983

Regulation of high density lipoprotein receptor activity in cultured human skin fibroblasts and human arterial smooth muscle cells.

Cultured human skin fibroblasts and human arterial smooth muscle cells possess high-affinity binding sites specific for high density lipoproteins (HDL). Results from the present study demonstrate that binding of HDL to these sites is up-regulated in response to cholesterol loading of cells. When fibroblasts or smooth muscle cells were preincubated with nonlipoprotein cholesterol, cellular binding of 125I-HDL3 was enhanced severalfold. This enhancement was sustained in the presence of cholesterol but was readily reversed when cells were exposed to cholesterol-free medium. The stimulatory effect of cholesterol treatment was prevented by cycloheximide, suggesting the involvement of protein synthesis. Kinetic analysis of HDL3 binding showed that prior exposure to cholesterol led to an induction of high-affinity binding sites on the cell surface. In the up-regulated state, the apparent dissociation constant (Kd) of these sites was approximately 2 micrograms protein/ml. Competition studies indicated that the HDL binding sites recognized either HDL3 or HDL2 but interacted weakly with low density lipoprotein (LDL). Exposure of cells to lipoprotein cholesterol in the form of LDL also enhanced HDL binding by a process related to delivery of sterol into cells via the LDL receptor pathway. Enhancement of HDL binding to fibroblasts by either nonlipoprotein cholesterol or LDL was associated with an increased cell cholesterol content, a suppressed rate of cholesterol synthesis, decreased LDL receptor activity, and an enhanced rate of cholesterol ester formation. A comparison of HDL3 binding with the effects of HDL3 on cholesterol transport from cells revealed similar saturation profiles, implying a link between the two processes. Thus, cultured human fibroblasts and human arterial smooth muscle cells appear to possess specific receptors for HDL that may function to facilitate cholesterol removal from cells.

Arteries↗
PubMed1982

Chylomicronemia syndrome. Interaction of genetic and acquired hypertriglyceridemia.

Chylomicrons accumulating in plasma obtained after an overnight fast are always abnormal and can be detected in association with triglyceride levels above 1000 mg per dl. The chylomicronemia syndrome is associated with marked hypertriglyceridemia (plasma triglyceride level above 2000 mg per dl), abdominal pain or pancreatitis, eruptive xanthomata, lipemia retinalis, dyspnea, mental aberrations, and other minor findings. The marked hypertriglyceridemia is usually due to the interaction of a common familial form of hypertriglyceridemia and a common acquired form of hypertriglyceridemia secondary to another disease, drug, or alcohol. Rarely, genetic abnormalities in lipoprotein lipase are the cause of the marked hypertriglyceridemia. Therapy that successfully lowers plasma triglyceride levels is associated with clearing of the symptoms and signs of the chylomicronemia syndrome and prevention of its recurrence.

Abdomen↗
PubMed1981

The effect of hydrocortisone on cholesterol metabolism of cultured human skin fibroblasts.

Hydrocortisone in physiologic concentrations resulted in a reduction in sterol synthesis by cultured normal human skin fibroblasts. These changes were observed when [14C]acetate, [14C]octanoic acid and 3H2O were used as precursors. However, the incorporation of [3H]mevalonic acid lactone into digitonin-precipitable sterols was not affected by hydrocortisone, suggesting that hydrocortisone inhibits sterol synthesis at a site prior to the formation of mevalonic acid. In contrast, the activity of hydroxymethylglutaryl-CoA reductase was stimulated several-fold by the hormone. Thus, the inhibitory effect of hydrocortisone on the cholesterol synthetic pathway may be on hydroxymethylglutaryl-CoA synthase.

Acetates↗
PubMed1981

Retro-endocytosis of low density lipoprotein by cultured bovine aortic smooth muscle cells.

Cultured bovine aortic smooth muscle cells, pretreated with 125I-labelled low density lipoprotein (LDL), rapidly released significant amounts of the lipoprotein as trichloroacetic acid-precipitable material during a subsequent chase period. The time and temperature dependence of this release process and its insensitivity to heparin-pretreatment of equilibrated cells suggest that LDL was regurgitated from cells by a rapid process that we have termed 'retro-endocytosis'. The total amount of lipoprotein released from cells equilibrated at 37 degrees C with 125I-labelled LDL was approximately 20% of the amount degraded, pointing to the existence of a small pool of material which was distinct from the lysosomal pathway. To quantify the flux of LDL through retro-endocytosis, the fate of surface-bound lipoproteins was analyzed. Cells, pretreated with 125I-labelled LDL at 4 degrees C, regurgitated about 50% of the initial surface-bound LDL during a chase period at 37 degrees C and degraded the remainder more slowly through the lysosomal pathway. The involvement of LDL-receptors was implicated because retro-endocytosis was a saturable process and was affected by up- and down-regulation. The apolipoprotein of the released LDL showed little proteolytic modification as analyzed by gel filtration. We conclude that in a steady-state situation the fraction of LDL that passes through the retro-endocytosis pathway is of the same order as that which is directed through the lysosomal system.

Animals↗
PubMed1981

Uptake of chylomicron remnants causes cholesterol accumulation in cultured human arterial smooth muscle cells.

Chylomicron remnants (Sf greater than 100) were prepared by treating human chylomicrons (Sf greater than 400) with human post heparin plasma. Chylomicron remnants recovered after 70-80% of chylomicron triacylglycerol was hydrolyzed, suppressed LDL-receptor activity and increased cell cholesterol esterification to the same extent as did LDL when added to cultured human arterial smooth muscle cells at an equal cholesterol concentration. Cell cholesterol mass increased 36% after incubation with 25 micrograms LDL cholesterol/ml and 35% with 25 micrograms chylomicron-remnant cholesterol/ml. Addition of 30 microM chloroquine plus LDL or chylomicron remnants further increased cholesterol content of cells (74% and 87%, respectively) and caused a significant rise in cell esterified cholesterol (344% and 369%, respectively). Cholesterol content per unit of apolipoprotein B mass of remnants was 2-3-fold higher than that of LDL. Therefore, if lipoprotein particles were added at equivalent apolipoprotein B mass chylomicron remnants increased cell cholesterol content and cholesterol esterification and suppressed LDL receptor activity significantly more than did LDL. This suggests that an additional determinant, presumably apolipoprotein E, is important for receptor recognition of chylomicron remnants. These results may be relevant to the delivery of chylomicron-derived cholesterol to arterial cells proposed as a feature of atherogenesis.

Aorta, Thoracic↗
PubMed1981

Receptor-dependent uptake of human chylomicron remnants by cultured skin fibroblasts.

Human chylomicrons were isolated from plasma from a subject with familial hypertriglyceridemia and converted to chylomicron remnants by incubation with postheparin plasma. The interaction of these apolipoprotein E-containing, cholesterol-rich human chylomicron remnants with cultured skin fibroblasts was studied. Chylomicron remnants were internalized by skin fibroblasts as a unit, mainly via the low density lipoprotein (LDL)-receptor pathway, resulting in increased cell cholesterol content. After entering the fibroblast, chylomicron remnants stimulated cholesterol esterification, suppressed 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, and down-regulated LDL receptor activity similar to the action of LDL. As a function of increasing lipolysis, remnant particles were progressively more effectively taken up by skin fibroblasts, despite a decrease in the apolipoprotein E content per lipoprotein particle. Remnant particles produced after hydrolysis of 70 to 80% of chylomicron triglyceride increased cell cholesterol content to an amount nearly identical to that observed with LDL when the two lipoproteins were incubated at an equal cholesterol concentration. However, when incubated on the basis of equal particle number, chylomicron remnants were 2 to 3 times more effective than LDL in delivering cholesterol to the cells. These results suggest that chylomicron remnants play a role in the regulation of postabsorptive cholesterol homeostasis in nonhepatic cells, and possibly in the pathogenesis of atherosclerosis.

Biological Transport↗
PubMed1981

High density lipoprotein composition in insulin-dependent diabetes mellitus.

Although atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in insulin-dependent diabetics, plasma levels of high density lipoprotein (HDL) cholesterol (an independent "negative" risk factor for ASCVD) have been reported to be normal or high. To test whether alterations in HDL composition might increase potential risk of insulin-dependent diabetics to ASCVD, their major constituent apolipoproteins, A-I and A-II, were measured and compared with levels in controls. HDL cholesterol levels were slightly higher (P = NS) in diabetics than in controls. The HDL cholesterol/LDL cholesterol ratio (an inverse index of relative risk of developing ASCVD) was significantly higher in diabetic men than in controls (P less than 0.02). HDL composition differed markedly in diabetics and controls: the apolipoprotein A-I/A-II ratio was significantly higher (P less than 0.001) in both diabetic men and women (diabetic men--4.1 +/- 0.5, mean +/- SD, controls 3.6 +/- 0.4; diabetic women--4.6 +/- 0.4, controls 3.9 +/- 0.5). Subsequent analysis of plasma from four patients by analytic ultracentrifugation demonstrated a high correlation (r = 0.993, P less than 0.01) between the apolipoprotein A-I/A-II ratio and HDL2, the cholesterol-rich lighter subclass of HDL thought to be the group of particles involved in reduced risk of ASCVD. Therefore, the alteration of HDL composition in insulin-dependent diabetics appears similar to that associated with reduced risk in nondiabetics. Thus, whether a genetic or acquired abnormality, the high apolipoprotein A-I/A-II ratio in insulin-dependent diabetics does not appear to counteract their increased risk of developing ASCVD.

Adolescent↗
PubMed1981

Acceleration of low-density lipoprotein catabolism in man by total parenteral nutrition.

Since insulin enhances the catabolism of low-density lipoprotein (LDL) by cultured human cells, a potential role of insulin in the regulation of plasma LDL levels in man is suggested. To evaluate the possible effect of insulin on LDL catabolism in vivo, the disappearance rates of injected 125I-labeled autologous LDL were determined before and after endogenous hyperinsulinemia was evoked by total parenteral nutrition. Multicompartmental analysis of plasma decay curves showed a 26% increase in the fractional catabolic rate of LDL after total parenteral nutrition was started. An associated reduction of plasma cholesterol levels resulted from changes in both LDl and high-density lipoprotein. These results suggest that the reduction of LDL levels during total parenteral nutrition is at least partly accounted for by enhanced LDL catabolism. It is postulated that the enhanced LDL catabolism may result from the hyperinsulinemia that accompanies total parenteral nutrition, via insulin stimulation of receptor-mediated LDL catabolism.

Cholesterol↗