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Adult↗
Biomedical subjects
Y Stein
Publications and source records attributed to Y Stein.
Biological and environmental sources of familial aggregation of blood pressure: the Jerusalem Lipid Research Clinic.
Genetic and cultural determinants of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were estimated using a path model on a sample of families examined in the Jerusalem Lipid Research Clinic. This model involves 10 parameters to be estimated from a total of 16 correlations (leaving ample degrees of freedom to test the goodness-of-fit). The general model fitted SBP (X2(6) = 6.95, p = 0.33) and DBP (X2(6) = 5.44, p = 0.49) very well. Both genetic (h2) and cultural (c2) components of inheritance were statistically significant for both blood pressure variables. Under the most parsimonious model, genetic heritabilities (h2) were estimated to be 0.20 and 0.28 for SBP and DBP respectively. Cultural heritability (c2) was 0.12 for SBP and 0.08 for DBP. A significant fraction of the estimate for cultural inheritance was due to a sibling environmental effect not mediated through their parents. Within this population genetic factors, common environmental factors and concomitant variables such as sex, age and origin explained about 40% of blood pressure variability. Most of the variance appears to be due to unmeasured environmental factors and errors of measurement.
Adolescent↗
Familial aggregation of body mass index in ethnically diverse families in Jerusalem. The Jerusalem Lipid Research Clinic.
Familial aggregation of body mass index in different ethnic populations was studied in a sample of nearly 4000 families resident in Jerusalem. Covariate adjustments were applied to body mass index (BMI) to adjust for variation in means and variances with sex, age and origin and for the effect of education, socioeconomic status and seasonality. The analyses were done separately in each of the origin groups categorized according to the parents' country of birth (Europe, Asia, North Africa, Israel/mixed origin), in order to account for the heterogeneity among the groups. Parent-child correlations were generally homogeneous across the origin groups. Sibling correlations for BMI differed to a greater extent among the groups. The highest correlation was observed in the Asian group (r = 0.49) and the lowest in the North African group (r = 0.16). Pooled correlations among biological relatives across the origin groups were highly significant. Spouse correlation, although significant was smaller, suggesting a stronger influence of genes than shared environment in the determination of the trait. Father-child correlation was significantly higher (r = 0.25) than mother-child value (r = 0.19), suggesting a possible paternal influence on BMI. There was also asymmetry in parent-offspring correlations by the sex of the offspring. Sibling correlation was higher (r = 0.33) than parent-offspring correlation (r = 0.22), suggesting that shared environment within generations tended to have some importance.
Adolescent↗
Metabolic fate and effect on cholesterol removal of liposomes prepared from 1,3-di-O-octadecenylglycero-2-phosphocholine studied in vivo and in vitro.
Available methodology was adapted to synthesize a labeled diether analog of 2-phosphatidylcholine (1,3-di-O-9'-cis-[9',10' (n)-3H]octadecenylglycero-2-phosphocholine [( 3H]DOE-2-PC). Unilamellar liposomes prepared by sonication from this phospholipid were injected into rats and, 4 h later, 65-78% of injected label was recovered in the liver. Thereafter, liver radioactivity disappeared with a half-life of 2-3 days. The radioactivity lost from the liver was recovered in the feces and in bile. Analysis of liver radioactivity showed that at all time intervals examined (4 h to 3 days after injection), 90% of the label remained as phospholipid. These findings provide evidence that this structural isomer is not readily metabolized, but is fairly rapidly eliminated from the liver. Of the 10% recovered as neutral lipid, 70% comigrated with diacylglycerol and 30% with triacylglycerol. Similar results were obtained when human hepatoma G2 cells in culture were incubated with [3H]DOE-2-PC liposomes. Following incubation of liposomes with liver homogenates, up to 10% conversion of [3H]DOE-2PC to neutral lipid occurred at pH 4.6, but not at pH 7.4. These data show that conversion of [3H]DOE-2-PC to dialkenylglycerol is catalyzed by a lysosomal enzyme. In separate experiments with cultured cells, sonicated dispersions of DOE-2-PC were mixed with high-density apolipoprotein and were shown to enhance markedly cellular cholesterol efflux. This novel diether phospholipid fulfills some of the criteria required of liposomes for their ability to remove cholesterol from the periphery as well as for drug delivery to the liver, i.e., stability in the circulation, marked hepatic uptake, slow metabolism, and elimination from the body.
Animals↗
Preferential binding of [3H]cholesteryl linoleyl ether-HDL3 by bovine adrenal membranes.
Membranes isolated from bovine adrenal cortex, incubated with human high-density lipoproteins (HDL3), labeled with 125I and [3H]cholesteryl linoleyl ether, showed preferential binding of [3H]cholesteryl linoleyl ether. The preferential binding was Ca2+ independent, temperature sensitive and was slightly increased after phospholipase C or pronase treatment. Reduction of membrane phosphatidylcholine by phospholipase A2 resulted in a marked increase in the binding of the entire HDL3 particle and a relative decrease in preferential binding of [3H]cholesteryl linoleyl ether. These findings suggest that the presence of intact phospholipid in the membrane plays an important role in the magnitude of the preferential binding.
Adrenal Cortex↗
Enhanced release and synthesis of lipoprotein lipase in rat heart cell cultures exposed to high concentrations of Hepes.
While attempting to optimize conditions for synthesis of lipoprotein lipase by cultured heart cells, we encountered an unexpected rise in enzyme activity when media were supplemented inadvertently with 100 mM Hepes buffer (4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid). This finding was further investigated and optimal results were obtained at pH 7.0-7.2. The increase in lipoprotein lipase activity was time dependent; after 3-6 h there was a rise in medium activity but cellular activity increased only after 24 h. The increased enzyme activity was defined as lipoprotein lipase by inhibition with antiserum to rat adipose tissue lipoprotein lipase. A 72-h exposure to Hepes resulted in a 30% increase in the incorporation of [35S]methionine into cellular proteins and a 2-fold increase into heparin-releasable proteins. Using heparin Sepharose chromatography and stepwise elution, a lipoprotein lipase enriched fraction was recovered with 2 M NaCl. The amount of [35S]methionine and [3H]galactose incorporated into protein of this fraction derived from Hepes-treated cells was 2-6-fold that of controls. A 4-fold increase in cellular lipoprotein lipase mass in Hepes-treated cells was shown by immunoblotting. Results obtained with Hepes-conditioned medium suggest the presence of cell-derived compounds that enhance release and subsequent synthesis of lipoprotein lipase. The effect of Hepes-conditioned medium on lipoprotein lipase resembled to some extent that of the addition of heparin. Therefore, it appears that when Hepes is first added to the culture medium, it might promote a release of heparan sulfate or related compounds, possibly by virtue of its negatively charged sulfonic acid residue. The accumulated heparan sulfate could then promote a sustained release of lipoprotein lipase into the culture medium which in turn leads to increased enzyme synthesis.
Animals↗
Studies on the in vivo transfer of retinoids from parenchymal to stellate cells in rat liver.
Studies were conducted to examine the in vivo transfer of chylomicron (dietary) retinoid from rat liver parenchymal to stellate cells. We specifically addressed the question of whether chylomicron retinyl ester is transferred directly from hepatic parenchymal to stellate cells without first undergoing hydrolysis. [14C]Retinyl palmitate and its non-hydrolyzable ether analog, retinyl [3H]hexadecyl ether, were utilized to answer this question. Chylomicrons labeled with these retinoids were injected intravenously into rats. Liver cell fractions, highly enriched in parenchymal or in stellate cells, were isolated 0.5 h, 4.5 h and 24 h after chylomicron injection. The ratio of 3H: 14C found in parenchymal cell preparations 4.5 h after injection was 1.8 times the ratio for the injected chylomicrons, and 24 h postinjection the ratio had increased to 2.5 times that of the chylomicrons. In the stellate-cell-enriched preparations the 3H: 14C ratio was found to be 0.39, 0.29, and 0.23 times the ratio found in the injected labeled chylomicrons at 0.5 h, 4.5 h and 24 h after injection respectively. From the levels of 14C observed in the isolated stellate cells, it is estimated that 0.5 h postinjection the stellate cells contained approximately 34% of the 14C (i.e. the retinol injected as chylomicron retinyl ester) present in the liver. By 4.5 h the 14C present in isolated stellate cells had risen to approximately 41% of that present in the total liver, and 24 h after injection approximately 55% of hepatic total 14C was found in the stellate cells. These findings suggest that chylomicron retinyl ester is not transferred directly from the parenchymal to stellate cells without first undergoing hydrolysis to retinol.
Animals↗
Preferential uptake of cholesteryl ester-HDL by cultured macrophages.
The interaction between HDL and macrophages in culture was studied using HDL labeled with 125I and with [3H]cholesteryl linoleyl ether. Mouse peritoneal macrophages and the macrophage-like cell lines J-774 and CT2, of mouse origin, took up and metabolized rat HDL and human HDL3. In all 3 cell types using both rat and human HDL, the uptake of the cholesteryl ester moiety as measured with the nondegradable cholesteryl ether analog, was 2-5-fold higher when compared to the protein moiety. Modulation of the cholesterol content of the cultured macrophages affected the uptake of both protein and lipid moieties of HDL to the same extent. When the macrophages had interacted with the labeled HDL for 5 h and were post-incubated for 20 h, the amount of [125I]HDL which reappeared in the post incubation medium was twice that of [3H]cholesteryl linoleyl ether-HDL. The site from which the HDL may have returned to the culture medium was tentatively localized to the trypsin-releasable, cell surface-related compartment. The present results indicate that interaction between macrophages and HDL may result in some loss of cholesteryl ester and possibly render the particle more receptive for cellular cholesterol removal.
Animals↗
Religious observance and plasma lipids and lipoproteins among 17-year-old Jewish residents of Jerusalem.
The association of religious observance and plasma lipids and lipoproteins was studied in a sample of 673 Jewish residents of Jerusalem ages 17-18 years. Religious observance was classified according to the parents' ranking of their perceived degree of religiosity. The study group included children whose parents were orthodox Jews who pedantically observed religious commandments, children of traditional parents who observed some of the rules, and children of nonobservant secular parents. Plasma levels of cholesterol, triglyceride, and low-density lipoprotein were higher in secular children than in the orthodox group. These associations were independent of sex, origin, social class, body mass, and season. High-density lipoprotein cholesterol was somewhat higher in the orthodox group than in the secular children although this difference was not statistically significant. Regression analysis showed that offspring's environment and parental phenotype were the most important predictors of lipid concentrations in adolescents. The association of religious observance with plasma lipids and lipoproteins, however, was independent of parental phenotype lipid values and the contribution of offspring and parents' environment. These findings are consistent with similar differences in plasma lipids described previously among the parents, as well as the lower incidence of myocardial infarction in the orthodox religious group, which has been shown in the Israeli adult population.
Adolescent↗
Parent-offspring aggregation of plasma lipids in selected populations in North America and Israel. The Lipid Research Clinics Prevalence Study.
Parent-offspring associations of total cholesterol and triglycerides were compared between family dyads in six North American populations examined between 1972 and 1976 as part of the North American Lipid Research Clinics Prevalence Study and those from families examined between 1976 and 1979 at the Lipid Research Clinic located in Jerusalem. Common study design, protocol, and laboratory techniques were used by all Lipid Research Clinics. The authors first examined homogeneity of familial correlations across clinics in the North American population and across origin groups in the Israeli sample. In general, correlations were homogeneous across clinics and origin groups, except for parent-daughter pairs for triglycerides in North America. The pooled familial correlations were similar in the two study populations. There was no asymmetry in parent-offspring correlations by the sex of the offspring. The pooled mother-child correlations were significantly higher than father-child values in the North American sample only. The strength of parent-offspring similarity showed no consistent pattern of change with level of education of parents in either study group. Patterns of familial similarity are discussed in relation to genetic, cultural, and environmental differences between the two study populations.
Adolescent↗
Peripheral vascular disease in a middle-aged population sample. The Jerusalem Lipid Research Clinic Prevalence Study.
Peripheral artery status and prevalence of peripheral vascular disease were studied in a sample of 1,036 men and 556 women, residents of Jerusalem. Ankle blood pressures determined by the Doppler ultrasound technique (Parks Electronic Lab, USA), were higher in men than in women and increased with age. In a multivariable regression analysis, systolic blood pressure and plasma cholesterol levels were significantly and inversely related to the ankle/arm blood pressure in men, and alcohol intake was inversely associated in women. The prevalence of peripheral vascular disease, as determined by symptoms of intermittent claudication, was 1.3% in men and 1.8% in women; absent pedal pulses were found in 1.1% of the men and in 2.0% of the women; leg pain on the treadmill was a reason for termination of exercise in 3.7% of the men and in 5.4% of the women and an ankle/arm blood pressure ratio of less than 0.90 in 4.2% of the men and in 5.4% of the women. The overlapping of the diagnostic criteria was low. No consistent determinants of the various measures of peripheral vascular status were found. In multivariable logistic models, cigarette smoking was significantly associated with intermittent claudication [Odd ratio (OR) = 3.03, 95% confidence interval (CI) 1.27 to 7.26], age was associated with leg pain on the treadmill (OR = 1.91, 95% CI 1.08 to 3.40 in men and OR 3.52, 95% CI 1.52 to 8.16 in women), body mass index was associated with absent and diminished pulses in women (OR = 1.61, 95% CI 1.07 to 2.42, systolic blood pressure was associated with an ankle/arm ratio of less than 0.90 in men (OR = 1.35, 95% CI 1.01 to 1.81), and glucose was associated with absent and diminished pulses in women (OR = 1.20, 95% CI 1.00 to 1.44).
Adult↗
[Reverse cholesterol transport].
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Animals↗
The role of apolipoproteins of HDL in the selective uptake of cholesteryl linoleyl ether by cultured rat and bovine adrenal cells.
Rat adrenal cells in culture were used to study the uptake of cholesteryl linoleyl ether [( 3H]cholesteryl linoleyl ether), a nonhydrolyzable analog of cholesteryl ester. When [3H]cholesteryl linoleyl ether was added in the form of liposomes, its uptake was enhanced by adrenocorticotropin (ACTH) and by addition of milk lipoprotein lipase and interfered by heparin. When the adrenal cells were incubated with homologous [3H]cholesteryl linoleyl ether-HDL, ACTH treatment also resulted in an increase in [3H]cholesteryl linoleyl ether uptake. The uptake of [3H]cholesteryl linoleyl ether was in excess of the uptake and metabolism of 125I-labeled HDL protein and was not sensitive to heparin. Unlabeled HDL or delipidated HDL reduced very markedly the uptake of [3H]cholesteryl linoleyl ether, while addition of phosphatidylcholine liposomes had little effect. Attempts were made to deplete and enrich the adrenal cells in cholesterol and, while depletion resulted in a decrease in [3H]cholesteryl linoleyl ether-HDL uptake, enrichment of cells with cholesterol had no effect. Among the individual apolipoproteins tested, apolipoprotein A-I and the C apolipoproteins reduced [3H]cholesteryl linoleyl ether uptake, while apolipoprotein E was not effective. Since the labeled ligand studied was a lipid, these effects could not be due to an exchange of apolipoproteins, but indicated competition for binding sites. Preferential uptake of human [3H]cholesteryl linoleyl ether-HDL3 by bovine adrenal cells was found when compared to the uptake and metabolism of 125I-labeled HDL. The present results suggest that the preferential uptake of HDL cholesteryl ester (as studied with [3H]cholesteryl linoleyl ether) requires an interaction between the apolipoproteins of HDL and cell surface components.
Adrenal Glands↗
The role of apolipoprotein A-IV in reverse cholesterol transport studied with cultured cells and liposomes derived from an ether analog of phosphatidylcholine.
Cholesterol efflux was studied in a model system in culture using apolipoproteins and phospholipids added in the form of liposomes at concentrations expected to be present in the extracellular fluid. Fibroblasts were seeded in medium containing [3H]cholesterol-labeled serum, grown till confluent, and the [3H]cholesterol efflux was studied in serum-free medium. Addition of delipidated HDL apolipoprotein resulted in a very low release of [3H]cholesterol, which did not increase with time of exposure or concentration of apolipoproteins. Addition of increasing amounts of HDL apolipoprotein to liposomes prepared from either dioleoylphosphatidylcholine (PC) or its nonhydrolysable ether analog, dioleylphosphatidylcholine (DOEPC) resulted in a 3-5-fold increase of [3H]cholesterol efflux, over that achieved with liposomes alone. This model system permitted the test of the putative role of apolipoprotein A-IV in cholesterol removal from cells. The ability of apolipoprotein A-IV to enhance [3H]cholesterol efflux from cells by DOEPC liposomes was compared to that of apolipoproteins A-I, E and C, which were added at equimolar concentrations. At nM concentrations, apolipoproteins A-IV, A-I and E were equally able to enhance cholesterol efflux, while C apolipoproteins were less effective at these low concentrations. Mixtures prepared from apolipoprotein A-IV, A-I and E and PC or DOEPC liposomes were equally effective in cholesterol removal, while phosphatidylethanolamine liposome apolipoprotein mixtures had a much lower capacity. The present study provides the first evidence that apolipoprotein A-IV can play a role in reverse cholesterol transport as was suggested on the basis of high concentrations of this apolipoprotein in nonlipoprotein form in plasma and extracellular fluid. The efficacy of DOEPC liposomes to serve as cholesterol acceptors might be of potential value for enhancement of reverse cholesterol transport in vivo.
Apolipoprotein A-I↗
Beta-adrenergic stimulation enhances translocation, processing and synthesis of lipoprotein lipase in rat heart cells.
Cells isolated from newborn rat hearts were cultured for 10-14 days, and lipoprotein lipase activity was present in an intracellular and heparin-releasable pool. Treatment of the cultures with 10(-7) M isoproterenol for 3 min resulted in a 3-fold increase in heparin-releasable lipoprotein lipase and a concomitant decrease in residual cellular enzyme activity. Similar results were obtained by treatment with dibutyryl cAMP. Treatment with isoproterenol or dibutyryl cAMP for 2 h affected glycosylation of immunoadsorbable lipoprotein lipase, so that the ratio of [3H]galactose to [14C]mannose in the heparin-releasable enzyme increased from 3.8 (control) to 13.0 (isoproterenol-treated). The change in the ratio of the sugars in the cellular fraction of the enzyme was from 3.1 to 9.9. 2 h treatment with isoproterenol did not enhance new enzyme synthesis, as determined by incorporation of [3H]leucine into immunoadsorbable lipoprotein lipase. 24 h after addition of either isoproterenol or dibutyryl cAMP to the culture medium, stimulation of enzyme synthesis was demonstrated. The present results permit three effects of isoproterenol on lipoprotein lipase to be distinguished: stimulation of translocation from a cellular to heparin-releasable pool; enhanced processing of mannose residues and terminal glycosylation; stimulation of synthesis of enzyme protein.
Animals↗
Characterization of the lipoprotein lipase in the functional pool of rat heart by immunoblotting.
Rat hearts were perfused with heparin for 2 min at 4 degrees C. The lipoprotein lipase activity in the perfusate was inhibited by antiserum to rat adipose tissue lipoprotein lipase. By immunoblotting, the lipoprotein lipase derived from the functional pool of the heart was found to be a protein with an apparent Mr of 69 000. After incubation of the perfusate at 37 degrees C for 24 h an immunologically reactive protein with an apparent Mr of 28 000 was found. This protein is not a physiological derivative of the enzyme but a degradation product.
Animals↗
Heterogeneity in multifactorial inheritance of plasma lipids and lipoproteins in ethnically diverse families in Jerusalem.
Genetic and cultural determinants of total cholesterol (TC), triglyceride (TG), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), and HDL-C/TC were estimated utilizing a path model in a random sample of nearly 4,000 families examined in the Jerusalem Lipid Research Clinic. The analyses were done separately in each of the ethnic groups categorized according to the parents' country of birth (Europe, Asia, North Africa, and Israel/mixed origin) in order to identify the nature and sources of any heterogeneity among the groups. Both genetic (h2) and cultural (c2) components of inheritance were significant for all lipid variables in each of the ethnic groups. Under the most parsimonious model, estimates of h2 in the ethnic groups were .40-.55, .40-.51, .45-.50, .41-.48, and .42-.78 for TC, LDL-C, HDL-C, HDL-C/TC, and TG, respectively. The c2 ranged from 3% to 5% for TC and LDL-C and from 4% to 10% for HDL-C, HDL-C/TC, and TG. The major parameters of the path model were generally homogeneous across the origin groups. The h2 appeared to be higher in the Asian and c2 was slightly greater in the European group. The stronger sibling environmental effect in the Asia group, the somewhat lower transmission of environment in the North African group, and the lower correlation between spouse environments in the North African group were the major sources of the origin heterogeneity. Within this population, genetic factors appear to be the major determinants of lipid variations, suggesting relative homogeneity of the distribution of environmental determinants of plasma lipids.
Adolescent↗
Complex segregation analysis of low levels of plasma high-density lipoprotein cholesterol in a sample of nuclear families in Jerusalem.
Low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease (CHD). Therefore, assessment of the mode of inheritance of HDL-C is of importance. HDL-C concentrations in 3,074 nuclear families in the multiethnic Jerusalem Lipid Research Center study population were analyzed for possible involvement of major genes in determination of low levels of this trait. Complex segregation analysis under the mixed model of inheritance (major gene and multifactorial components) was performed on transformed HDL-C concentrations after adjustment for age, sex, and environmental measures. Evidence for segregation of a recessive major gene for depressed HDL-C, with an allele frequency of q = 0.06, in addition to multifactorial transmission (H = 0.45) was found in these families. Estimates from the mixed model were homogeneous across the different ethnic groups. When the substantial multifactorial background was excluded from the model, we found evidence for an additive (codominant) Mendelian gene (d = 0.48), which demonstrates the necessity of using the mixed model. Our previous results were inconclusive with respect to the involvement of a major gene in determination of high levels of HDL-C. However, we tentatively postulate an uncommon recessive gene for low levels of HDL-C in the Israeli population in addition to polygenic and environmental determinants.
Adolescent↗