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Biomedical subjects

W Patsch

Publications and source records attributed to W Patsch.

At least 109 records · Page 6Linked to original sources
PubMed1984

Effects of high cholesterol diets on rat plasma lipoproteins and lipoprotein-cell interactions.

High fat, high cholesterol diets do not produce atherosclerotic lesions in some animal species such as the rat; however, when combined with experimentally induced hypothyroidism, such diets do produce lesions. While the diets or hypothyroidism each induce significant alterations in plasma lipoproteins, the combination produces marked hypercholesterolemia. If the atherosclerosis is related to the hyperlipidemia, the combination regimen could be provoking changes in the structure or compositions of lipoproteins which are not noted with either regimen alone. To test this hypothesis, Sprague-Dawley male rats (approximately 250 g) were treated as follows: Diet(a) = chow + 5% lard and 0.3% Na taurocholate; Diet(b) = Diet(a) + 2% cholesterol; Diet(c) = Diet(b) + 0.1% propylthiouracil (PTU). The major findings were as follows. 1) With Diet(b), slow floating very low density lipoprotein (VLDL) (pre-beta) enriched in cholesteryl esters accumulated in plasma and low density lipoprotein (LDL) disappeared from its usual flotation position. 2) With Diet(c), changes in plasma concentration were more marked but were also qualitatively different. More VLDL accumulated, and distribution of VLDL was shifted toward even slower floating cholesteryl ester-rich particles. VLDL had "broad beta" mobility. Also, a beta-migrating intermediate density lipoprotein (IDL) population appeared. 3) Lipoprotein (d less than 1.019 g/ml) and zonal subfractions of d less than 1.019 g/ml lipoproteins (isolated from rats on cholesterol Diet (b] stimulated [3H]oleate incorporation into cholesteryl esters of fibroblasts and macrophages, while the d less than 1.019 g/ml fractions of 5% fat (Diet(a]-fed rats did not. 4) The major finding of this study was that identically prepared d less than 1.019 g/ml fractions of Chol + PTU-treated rats (Diet(c] were approximately 2.5-fold more stimulatory than the lipoproteins of cholesterol-fed rats. The results could not be explained by differences in cholesterol contents of the cholesterol-rich lipoproteins, but significant differences in the apoprotein compositions of the fraction were found which could be important. The most active fractions had higher apoBL/apoBS and apoE/apoC ratios than less active fractions. Thus, the combination regimen of cholesterol and PTU produced changes in lipoprotein structure and composition which enhanced the abilities of the lipoproteins to interact with cells. The results suggest that analysis of lipoprotein-cell interactions in vitro may be predictive of the atherogenic potential of lipoproteins in vivo and that euthyroidism in rat protects against atherogenic hyperlipidemia.

Animals↗
PubMed1983

Racial differences in plasma high-density lipoproteins in patients receiving hemodialysis. A possible mechanism for accelerated atherosclerosis in white men.

Among 346 nondiabetic patients receiving long-term hemodialysis, cardiovascular mortality was higher in white than in black men (P less than 0.02) but was similar between black and white women, despite the higher incidence of nephrosclerosis in black men and women (59 and 58 per cent vs. 8 and 10 per cent, respectively; P less than 0.0001). There were significant racial differences in plasma lipid and apoprotein levels in a subset of 100 of these patients. The white men had higher levels of plasma triglyceride and lower levels of high-density-lipoprotein (HDL) cholesterol, apoprotein A-I, and apoprotein A-II than black men; concentrations of HDL, apoprotein A-I, and apoprotein A-II were also lower in white than in black women. The distribution of the HDL subfractions HDL2, HDL3, and HDL3D, as determined by zonal ultracentrifugation, was normal in black and abnormal in white men receiving hemodialysis. HDL2 concentrations were higher in black than in white men by both zonal analysis (P less than 0.05) and polyanionic precipitation of the HDL subfractions (P less than 0.01). The distributions and concentrations of HDL2 and HDL3L were similar in black and white women. Thus, there are marked racial differences in HDL in male patients receiving hemodialysis. The abnormalities in HDL and the hypertriglyceridemia in the white men may explain their high rate of cardiovascular mortality.

Adult↗
PubMed1983

Effect of probucol on the composition of lipoproteins and on VLDL apoprotein B turnover.

We studied the effect of probucol on lipoprotein composition and VLDL apo B turnover. In 7 hypercholesterolemic subjects, probucol therapy lowered mean total cholesterol, HDL cholesterol and HDL triglycerides, raised LDL triglycerides and did not change LDL cholesterol. LDL cholesterol:LDL triglycerides mass ratios fell. In all 6 subjects studied by rate-zonal ultracentrifugation, the flotation rate of LDL decreased. The isolated LDL were depleted of cholesteryl esters relative to protein. Thus, there were changes in the physical and chemical properties of LDL. All 6 subjects had reductions in HDL2, with variable changes in HDL3 on zonal ultracentrifugation. Probucol did not cause significant alterations in VLDL apo B turnover in 4 patients. The results suggest that the alterations in HDL probably are not related to changes in the flux of VLDL plasma, but rather may be due to direct effects of the drug on HDL production or catabolism.

Adult↗
PubMed1983

ApoA-I/ApoA-II ratios in plasmas of vegetarians.

Diets low in fat and cholesterol and high in P/S ratio are accompanied by low HDL-cholesterol levels. Short-term experimental feeding of such diets demonstrates that the HDL2 fraction is reduced preferentially. In order to ascertain whether the HDL2 lowering effects persist over the long-term, apolipoprotein A-I/A-II ratios, which are indices of the HDL2 relative to HDL3 in plasma, were measured in three groups of vegetarians (n = 35) who had been eating vegetarian diets for 1 to more than 5 years varying in cholesterol contents from less than 10 to 300 mg/d, fat between 30% to 50% of calories, and P/S ratio between 0.7-2.5. Concentrations of apoA-I were lower in those eating the least cholesterol and the highest P/S ratio, ie, apoA-I correlated positively with dietary cholesterol (r = 0.38, P less than 0.05), and both apoA-I and the A-I and the A-I/A-II ratio correlated negatively with the ratio of polyunsaturated-to-saturated (P/S) fatty acids (r = -0.39, P less than 0.05, and r = -0.41, P less than 0.02, respectively). There was no significant correlation between apoA-I, apoA-II, the A-I/A-II ratio or the high-density lipoprotein cholesterol/apoA-I ratio and consumption of total calories, fat, protein, or carbohydrate. Since the A-I/A-II ratio is much higher in HDL2 than in HDL3, these data suggest that cholesterol intake and the P/S ratio are important long-term dietary determinants of plasma HDL2 levels. Thus, in vegetarians, despite a reduced risk of coronary heart disease, the high-density lipoprotein cholesterol (HDL-C) and especially HDL2 concentrations were low. More work is needed to elucidate this interesting paradox.

Adult↗
PubMed1983

Role of insulin in lipoprotein secretion by cultured rat hepatocytes.

To study the effect of insulin on lipoprotein synthesis and secretion by the liver, apoprotein and lipid levels were measured in primary rat liver cell cultures grown on fibronectin-coated dishes. Triglycerides, phospholipids, apoprotein (apo) B, apo-E, and apo-C-III3 all accumulated in culture media linearly for periods up to 20 h. During incubations, cellular triglyceride contents increased slightly, while cellular apoprotein and phospholipid contents remained constant. In the absence of insulin, rates of accumulation in media of triglycerides, apo-B, apo-C-III3, and apo-E were 2.5 +/- 0.3 micrograms/mg and 33 +/- 5, 24 +/- 3, and 162 +/- 32 ng/mg cell protein per h, respectively. On gel permeation chromatography and density gradient ultracentrifugation, the majority of apoproteins in media were found to be associated with very low density lipoproteins (VLDL) and very little eluted or sedimented with albumin. Incubations in the presence of 50-800 microU/ml of insulin resulted in dose-dependent decreases of triglyceride, phospholipid, apo-B, and apo-E accumulation in the media, paralleled by increases in the cellular contents of these lipoprotein components. The inhibitory effects of insulin on secretion were reversible. Levels of apo-C-III3 and albumin were not affected by insulin. In addition to decreasing secretory rates, the proportion of apo-B, apo-E, and apo-C-III3 associated with VLDL also decreased after the addition of insulin. Concomitantly, the proportion of apo-B eluting with LDL and apo-C-III3, and apo-E eluting near albumin increased. Control experiments, in which exogenous 125I-VLDL or endogenously labeled [14C]VLDL were added to cultures, revealed that the insulin-induced differences in VLDL accumulation and the lipid association of media apoproteins were not due to differences in the processing of VLDL by cells cultured in the presence or absence of insulin. Therefore, it appears that insulin may inhibit the secretion of VLDL perhaps by reducing the intracellular association of lipids and apoproteins.

Animals↗
PubMed1983

Effect of fatty acids on lipid and apoprotein secretion and association in hepatocyte cultures.

Increasing availability of free fatty acids (FFA) to liver results in enhanced rates of secretion of triglycerides in lipoproteins. However, as FFA uptake increases, triglyceride secretory rates reach a plateau and esterified fatty acids accumulate intracellularly, suggesting that something is limiting lipid transport out of the liver. One possibility could be the limited availability of apoproteins. To test this hypothesis, primary rat hepatocytes in culture were incubated with increasing amounts of FFA (0-2.1 mumol/dish) and the amounts of lipids and apoproteins inside the cells and in culture media were measured; the latter by specific radioimmunoassays. Media also were fractionated on Sepharose 2B and 6B columns and the elution profiles of apoproteins were obtained. With exposure to increasing amounts of free fatty acids, hepatocytes took up more fatty acids and intracellular levels of triglycerides rose (from 71 to 146 micrograms/mg cell protein). Concomitantly, media triglycerides nearly doubled (31 to 51 micrograms/mg). Incorporation of [3H]glyceride into cellular and media triglyceride also rose. However, levels of apoproteins A-I, B, C-III3, and E in cells and media were unchanged. The increasing amounts of triglycerides in media were present in larger particles, as demonstrated on gel permeation chromatography. The elution profiles of apoproteins B, C-III3, and E were altered in that a greater proportion of the apoproteins eluted with larger particles. Similar results were obtained when hepatocytes were preloaded with increasing amounts of FFA over 12 h and analyses of cells and media were carried out 8 and 22 h after removal of fatty acids from the media. During loading of cells, accumulation of cellular triglycerides was directly related to media FFA concentrations. During unloading, triglyceride secretory rates were related to cellular triglyceride levels. At higher triglyceride secretory rates larger particles were secreted and a greater proportion of apoproteins was associated with the larger particles, but total amounts of apoproteins in the system did not change. These data lead us to suggest that enhanced rates of apoprotein synthesis need not occur in the response to acute changes in hepatic lipid transport, rather, increased secretion of lipid is brought about by augmented intracellular lipid apoprotein association.

Animals↗
PubMed1983

Increases in dietary cholesterol and fat raise levels of apoprotein E-containing lipoproteins in the plasma of man.

Previous studies from this laboratory have determined that diets containing the usual amounts of fat to which are added 750-1500 mg/day cholesterol elevate the plasma cholesterol concentration by variable amounts, depending upon the ratio of polyunsaturated to saturated fatty acids (P/S ratio) of the diet. Diets with P/S ratios of 0.25-0.4 are accompanied by elevations of low density lipoprotein (LDL) cholesterol, whereas diets with a P/S ratio of 2.5 produce no significant changes in cholesterol levels. On the low P/S ratio diets, the structure, composition, and interaction with cultured fibroblasts of LDL are not significantly changed. Plasma high density lipoprotein (HDL) cholesterol levels remain constant, but HDL2 increase relative to HDL3. In the present study, not only dietary cholesterol but also total dietary fat was altered. Six normal young men were fed a basal diet consisting of 18% protein, 51% carbohydrate, and 30% fat, containing 250 mg/day cholesterol. After 2 weeks, an experimental diet consisting of 18% protein, 42% carbohydrate, and 39% fat, containing 1760 mg/day cholesterol, was fed for 4 weeks. The P/S ratios of both diets were about 0.4. Plasma samples were taken twice during each dietary period from 12- to 14-h-fasted subjects and analyzed for their contents of lipoprotein lipids. Plasma levels of LDL and HDL cholesterol increased by 30 and 13 mg/dl, respectively; total and very low density lipoprotein (VLDL) triglyceride concentrations were unaltered. The plasma concentrations of apoproteins (apo) B, E. and A-I, but not A-II, were elevated. Plasma samples also were studied by zonal ultracentrifugation, gel permeation column chromatography, and Pevikon electrophoresis. Although on zonal ultracentrifugation the total concentrations of LDL were increased, the flotation properties and chemical compositions of LDL were not changed. By contrast, HDL2 and HDL3L concentrations increased, and HDL2 became enriched with cholesteryl esters. On gel permeation chromatography, with the subjects on the basal diet, plasma cholesterol eluted in two peaks, corresponding to LDL and HDL. The sizes of the peaks increased on the experimental diet. ApoE eluted in two peaks: one at the leading edge of LDL (corresponding to VLDL or IDL) and the other in the area between LDL and HDL, corresponding to HDLC. On the experimental diet, the apoE peak between LDL and HDL increased. On Pevikon electrophoresis apoE migrated between the LDL and HDL bands. This apoE peak was increased on the experimental diet. These findings suggest that increasing the concentrations of both dietary cholesterol and total fat can increase the levels of plasma LDL, HDL2, and HDLC in fasting normal subjects. Thus, the concentrations of some putatively atherogenic as well as antiatherogenic lipoproteins increased in plasma, and the apparent paradox between the epidemiological and metabolic behaviors of some lipoproteins remains. Clearly, more work is needed to resolve the roles of various lipoproteins in plasma in atherosclerosis.

Adult↗
PubMed1983

Receptors for homologous plasma lipoproteins on a rat hepatoma cell line.

Hepatocytes express on their surfaces more than one class of receptors capable of mediating the internalization of lipoproteins. However, relatively little is known about the binding characteristics of hepatic receptors for various lipoproteins, about the regulation of the receptors, and about the consequences for intracellular lipid metabolism of uptake of lipoproteins via different classes of receptors. The aim of the present studies was to characterize the binding and degradation of various lipoproteins and their mutual competition for cellular processing. Since these kinds of studies may be more easily carried out in continuous established hepatoma cell lines than in nondividing primary hepatocyte cultures, we examined the lipoprotein receptor functions of a well differentiated rat hepatoma (H-35). Cells were grown to confluence in Eagle's minimal essential medium in 15% newborn calf serum. Medium then was changed to 15% lipoprotein-deficient serum for 44 hr before experiments. External binding of 125I-labeled rat plasma and intestinal lymph lipoproteins was assessed at 4 degrees C. Cellular uptake and degradation were assessed at 37 degrees C. Lipoproteins were isolated by fixed angle or zonal ultracentrifugation or by heparin affinity column chromatography and characterized as to their lipid and apoprotein compositions. Labeled low density (LDL), high density (HDL2), non-apoE-HDL, very low density lipoproteins (VLDL), and chylomicron remnants (CM-R) each manifested specific and saturable binding and degradation by the hepatoma cells. Competition experiments indicated that separate receptors were present for LDL, HDL2, and CM-R. Most of HDL2 appeared to be bound to the non-apoE-HDL receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Viscosity of culture medium as a regulator of synthesis and secretion of very low density lipoproteins by cultured hepatocytes.

It has been postulated that hyperlipidemia in the nephrotic syndrome is due to overproduction of lipoproteins and that low colloid osmotic pressure (due to hypoalbuminemia) triggers this. Secretion of very low density lipoproteins (VLDL) by cultured rat hepatocytes has been shown to be inhibited by albumin, globulins, and dextrans, but the effect did not correlate with osmolarity. In the present studies we tested the hypothesis that viscosity rather than osmolarity might be the parameter determining the effectiveness of macromolecules in inhibiting VLDL synthesis and secretion by cultured rat hepatocytes. Synthesis and secretion of VLDL was measured in terms of incorporation of [3H] glycerol into medium triglycerides and also from changes in the mass of secreted VLDL triglycerides and apoproteins. The viscosity of the culture medium was increased by addition of dextran-500, gelatin or methylcellulose MX 880. Synthesis and secretion of VLDL was inhibited in direct proportion to increasing viscosity. At a viscosity of 2, which is about that of normal plasma, VLDL secretion was reduced by 20%. An inhibition of 60-70% in secretion and 30-40% in synthesis of VLDL lipid and protein components was observed at a relative viscosity of approximately 3.7. This viscosity was obtained by addition of any of the following: 3% dextran, 3% gelatin, 0.2% methylcellulose, or a combination of 0.1% methylcellulose plus 2% gelatin. Thus, similar viscosities resulted in similar degrees of inhibition despite differences of up to 16-fold in mass concentration and up to 20-fold in osmolarity.

Animals↗
PubMed1982

Apolipoprotein E levels in vegetarians.

Vegetarians are known to have low lipoprotein lipid and apolipoprotein Al and B levels. Since dietary cholesterol has recently been shown to have important effects on apolipoprotein E (apo E) metabolism, we measured plasma apo E levels in three groups of vegetarians. Group I (n = 36) consumed less than 10 mg cholesterol daily and 42% of calories as fat (P:S ratio 2.6). Group II (n = 10) and Group III (n = 18) consumed 97 and 179 mg cholesterol daily, and 35% of calories as fat (P:S ratios 0.7 and 0.9) respectively. Compared to control values, vegetarian plasma cholesterol and triglyceride levels were decreased by 10%-30% and 30%-55%. Plasma apo E levels were decreased equally in all groups by 35% (2.4 +/- 0.1 mg/dl versus 3.6 +/0 0.1 mg/kl, P less than .001). Plasma apo E levels were increased in parallel with lipid levels in pregnant vegetarians but were not different from non-lactating vegetarians in postpartum lactating women. Decreased apo E levels did not correlate with relative body weight, P:S ratio or intake of fat, carbohydrates or protein. Since all vegetarian diets studied were low cholesterol diets, decreased cholesterol intake may contribute to the low apo E levels. The apparent modification of apo E metabolism by vegetarian diets may be important in mediating effects of lipid lowering diets on atherogenesis.

Apolipoproteins↗
PubMed1982

Effects of dietary cholesterol and fatty acids on plasma lipoproteins.

The effects of dietary cholesterol and fatty acids on low density and high density lipoproteins (LDL and HDL) were studied in 20 young men. After 2-3 wk of evaluations on ad lib. diets, basal diets, which consisted of 15% protein, 45% carbohydrates, 40% fat, and 300 mg/day of cholesterol, were given for 4-5 wk (Basal). The ratio of dietary polyunsaturated to saturated fatty acids (P/S) for different groups of subjects were 0.25, 0.4, 0.8, or 2.5. 750 and 1,500 mg/d of cholesterol were added to the basal diets as 3 and 6 eggs, respectively. Total cholesterol and LDL cholesterol were lower in all subjects on the basal diets than on the ad lib. diets. Addition of 750 mg cholesterol to the diet with P/S = 0.25-0.4 raised LDL cholesterol by 16 +/- 14 mg/dl to 115% of basal diet values (n = 11, P less than 0.01); 1,500 mg increased LDL cholesterol by 25 +/- 19 mg/dl to 125% (n = 9, P less than 0.01). On the diet with P/S = 0.8, 750 mg produced insignificant increases in LDL cholesterol, but 1,500 mg produced increases of 17 +/- 22 mg/dl to 115% of basal (n = 6, P less than 0.02). On the P/S = 2.5 diet, neither 750 nor 1,500 mg produced significant changes. Thus, both the cholesterol contents and P/S ratios of diets were important in determining LDL levels. The lipid and apoprotein compositions, flotation rates, molecular weights, and binding by cellular receptors of LDL were virtually unchanged by the addition of cholesterol to the diets high in saturated fat. These diets, therefore, caused an increase in the number of LDL particles of virtually unchanged physical and biological properties. On the diet with low P/S ratio, HDL2 rose, whereas this effect was absent on diets with high P/S ratios. The response of LDL to dietary manipulations is consonant with epidemiologic data relating diets high in cholesterol and saturated fat to atherogenesis. The response of HDL2, however, is opposite to that of its putative role as a negative risk factor. Further work is needed to clarify this interesting paradox.

Adult↗
PubMed1981

The effect of short-term feeding of a high carbohydrate diet on HLD subclasses in normal subjects.

Plasma HDL concentrations are effected by several perturbations, including certain dietary manipulations. In this study we have examined the effects of a one week ingestion of an isocaloric, fat-free, high-carbohydrate diet (CHO greater than 80% of calories) and the concentrations and compositions of plasma HDL subclasses. Eleven healthy normolipidemic volunteers (6 females, 5 males) took part in this study. Blood samples for lipoprotein analysis were drawn before and at the end of the dietary period and analyzed for lipoprotein lipid and apoprotein concentrations. Lipoproteins also were characterized by zonal ultracentrifugation. Our results show the following significant changes at the end of the dietary period: plasma concentrations of VLDL-TG, VLDL-cholesterol and total VLDL mass increased, whereas plasma concentrations of LDL-cholesterol, LDL mass and HDL-cholesterol and HDL mass, decreased. Plasma concentrations of apoprotein A1 decreased (from 133.3 +/- 7.7 to 108.1 +/- 8.6; mean +/- S.E.M., p less than 0.0004), and apoprotein A2 concentrations remained unchanged. This resulted in a drop in plasma ratio of ApoA1/ApoA2 (p less than 0.03). Since it has been shown that ApoA1/ApoA2 ratio is higher in HDL2 than HDL3, we examined the concentrations of these two subfractions, employing rate-zonal ultracentrifugation for their isolation. One week of ingestion of the study diet was followed by consistent decreases in HDL2 mass (from 84 +/- 15 to 44 +/- 16 mg/dl, mean +/- S.E.M.), with inconsistent changes in HDL3 mass, (from 254 +/- 18 to 222 +/- 13 mg/dl) resulting in significant decreases in HDL2/HDL3 mass ratio. Lipid analyses of these subfractions did not demonstrate major compositional changes. The alterations noted could be due to decreased HDL production, at least in part, but alterations in the interconversions of lipoproteins also could have played a role. The falls in HDL2 on a diet which should be "antiatherogenic" illustrate the difficulty of assessing the atherogenicity of any given diet solely by the changes it produces in the levels of circulating lipoproteins.

Adult↗
PubMed1980

Acid cholesterol ester and glycerol ester hydrolase activities. Evidence for the individuality of these enzymes in human mononuclear leucocytes.

Hydrolysis of cholesterol oleate and glycerol trioleate was measured in homogenates of human leucocytes at optimum pH of 4.0 and 5.25, respectively. Both enzyme activities appeared to reside in the 15,000 x g, 20-min fraction of mononuclear leucocytes. Solubilization of cholesterol ester hydrolase activity was strongly dependent on the detergent to protein ratio, showing optimal solubilization at weight ratios of 1.0 in cell homogenates and of 3.0 in the 15,000 x g, 20-min fraction, whereas solubilization of glycerol ester hydrolase was independent to protein ratio over the tested range of 0.3 to 5.8. Using a sequential solubilization procedure, about 60% of the granule proteins as well as 88% of glycerol ester hydrolase activity were solubilized at a detergent to protein ratio of 0.3, whereas cholesterol ester hydrolase activity was solubilized from the remaining membranes at a ratio of about 3.0. Thus, the acid glycerol ester hydrolase and acid cholesterol ester hydrolase were related to different proteins. Since solubilization of cholesterol ester hydrolase required drastic treatment, it is suggested that this enzyme is related to a protein within the lysosomal membrane.

Blood Platelets↗
PubMed1980

Guanfacine and glucose metabolism.

1. The effect of a single dose of guanfacine 1.0 mg intravenously on glucose metabolism was compared with placebo. Six men participated in the cross-over study. 2. An oral glucose tolerance test was performed 90 min after the administration of the medicaments. Guanfacine had no effect on blood glucose, insulin or the 'Insulinogenic index'.

Antihypertensive Agents↗