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Biomedical subjects

G S Getz

Publications and source records attributed to G S Getz.

At least 19 recordsLinked to original sources
PubMed1992

Human plasma lipoproteins regulate apolipoprotein E secretion from a post-Golgi compartment.

The molecular regulation of apolipoprotein E (apoE) synthesis and secretion is incompletely understood. In this study, we have examined the effect of human low density lipoprotein (LDL) on apoE mRNA and protein levels in HepG2 and other eukaryotic cells. Exposing HepG2 cells to LDL for times up to 4 h resulted in an increase in 35S-labeled apoE accumulation in the medium by 2.2-fold, relative to serum free controls (n = 10, p < 0.001), with no changes in apoE mRNA levels. Similar observations have been made in JeG-3 cells and Chinese hamster ovary cells stably transfected with human apoE cDNA constructs. These results indicate that the LDL effect operates at a post-transcriptional level. In pulse-chase experiments, the LDL effect on apoE accumulation in the media was observed when it was added only during the chase even in the presence of cycloheximide, indicating that LDL is functioning at a post-translational level. The use of brefeldin A (BFA), an agent that impedes protein transport from the endoplasmic reticulum to the Golgi apparatus, suggests that the LDL effect occurs in a post-Golgi compartment. The addition of protease inhibitors could not duplicate the effects of LDL on the apoE accumulation in the medium. ApoA-I accumulation in the medium of HepG2 cells, but not albumin, was also significantly increased by 1.9-fold (n = 5, p < 0.001).

Albumins↗
PubMed1992

Role of basal triglyceride and high density lipoprotein in determination of postprandial lipid and lipoprotein responses.

The present study reports on the interaction between basal triglyceride and high density lipoprotein (HDL) cholesterol in determining the magnitude of postprandial triglyceridemia. The vitamin A fat-loading test was used to label intestinally derived triglyceride-rich particles after a high fat meal in 18 subjects with low HDL cholesterol and 6 control subjects who had normal fasting triglyceride and HDL cholesterol levels. The patients with low HDL cholesterol were divided into 2 groups on the basis of their basal triglyceride concentrations; 11 had normal triglyceride levels, and 7 had elevated serum triglycerides (HTG). In the HTG-low HDL group, the incremental area under the triglyceride curve was significantly greater (P less than 0.0003) than that in the other 2 groups, between whom no significant differences in triglyceride response were observed. Retinyl palmitate levels measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction were also significantly greater in low HDL subjects with HTG, while the concentrations in low HDL subjects with normal triglyceride levels and control subjects were similar. Although basal HDL cholesterol levels in all study subjects were negatively correlated with the area under the incremental triglyceride curve (r = -0.42; P less than 0.05), this correlation was weak, in contrast to the correlation between fasting triglyceride levels and incremental triglyceride area (r = 0.56; P less than 0.005). Furthermore, basal HDL cholesterol levels did not correlate with the area under the chylomicron or nonchylomicron curves, whereas basal triglyceride levels were significantly correlated (P = 0.0001) with both of these variables. The HDL particles of both low HDL groups had a significantly higher proportion of triglyceride compared to the HDL particles in the control subjects. In conclusion, 1) fasting triglyceride levels are a more powerful indicator of the postprandial lipid response than basal HDL cholesterol in subjects with low HDL cholesterol levels; 2) patients with low HDL cholesterol levels do not preferentially accumulate chylomicron remnants after a meal unless they have coexisting hypertriglyceridemia; and 3) abnormalities in the levels of triglyceride-rich particles post-prandially are unlikely to be responsible for the increased incidence of atherosclerosis in low HDL patients who are normotriglyceridemic.

Blood Glucose↗
PubMed1991

Postprandial triglyceride response in type 1 (insulin-dependent) diabetes mellitus is not altered by short-term deterioration in glycaemic control or level of postprandial insulin replacement.

UNLABELLED: The effect of deteriorating glycaemic control on the lipoprotein responses to the ingestion of a high fat meal was investigated in seven normolipidaemic Type 1 (insulin-dependent) diabetic patients and the results were compared with corresponding responses in seven normolipidaemic control subjects. In addition, the importance of insulin in regulating the postprandial lipoprotein responses was examined by comparing the results obtained from the diabetic patients maintained on a basal infusion of insulin throughout the study with those obtained when a step-up, step-down insulin infusion was administered following the meal. Vitamin A was added to the test meal in all subjects to trace the metabolism of the chylomicron (Sf greater than 1000) and non-chylomicron (Sf less than 1000) fractions in the postprandial period. No differences in fasting and postprandial triglyceride levels nor in the concentration of the chylomicron and non-chylomicron fractions were observed between diabetic and control subjects. In the diabetic patients short-term (two-week) deterioration in glycaemic control did not have any adverse influence on the basal and postprandial lipid responses. However, while the amount of insulin administered after the meal in the diabetic patients did not have any effect on the postprandial triglyceride or chylomicron responses, the concentration of non-esterified fatty acids was significantly higher (p less than 0.0005) when only a basal infusion of insulin was administered. IN CONCLUSION: 1) Short-term deterioration in glycaemic control does not adversely affect lipoprotein concentrations in Type 1 diabetes. 2) Non-esterified fatty acids appear to be a more sensitive index of insulinization post-prandially than triglycerides.

Adult↗
PubMed1991

Induction of omega-oxidation of monocarboxylic acids in rats by acetylsalicylic acid.

The accumulation of dicarboxylic acids, particularly long chain, is a prominent feature of Reye's syndrome and diseases of peroxisomal metabolism. We assessed the omega-oxidation of a spectrum of fatty acids in rats and asked whether pretreatment of rats with aspirin, which is known to predispose children to Reye's syndrome, would affect omega-oxidation of long chain fatty acids. We found that aspirin increased liver free fatty acids and increased the capacity for omega-oxidation three- to sevenfold. Omega-oxidation of long chain substrate was stimulated to a greater degree than medium chain substrate and was apparent within one day of treatment, at serum aspirin concentrations below the therapeutic range in humans. The apparent Km for lauric acid was 0.9 microM and 12 microM for palmitate. We also found a difference in the storage stability of activity toward medium and long chain substrate. Saturating concentrations of palmitate had no effect on the formation of dodecanedioic acid, whereas laurate decreased but never eliminated the omega-oxidation of palmitate. 97% of the total laurate omega-oxidative activity recovered was found in the microsomes, but 32% of palmitate omega-oxidative activity was present in the cytosol. These results demonstrate that aspirin is a potent stimulator of omega-oxidation and suggest that there may be multiple enzymes for omega-oxidation with overlapping substrate specificity.

Animals↗
PubMed1991

Fasting hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid and lipoprotein abnormalities.

Postprandial lipoprotein metabolism may be important in atherogenesis and has not been studied in detail in noninsulin-dependent diabetes mellitus (NIDDM). We used the vitamin A fat-loading test to label triglyceride-rich lipoprotein particles of intestinal origin after ingestion of a high fat mixed meal containing 60 g fat/m2 and 60,000 U vitamin A/m2 in 12 untreated NIDDM subjects with normotriglyceridemia (NTG; triglycerides, less than 1.7 mmol/L), 7 untreated NIDDM subjects with moderate hypertriglyceridemia (HTG; triglycerides, 1.7-4.7 mmol/L), and 8 age- and weight-matched normotriglyceridemic nondiabetic controls. The postprandial triglyceride increment was greater in NIDDM with HTG (P = 0.0001) and correlated strongly in all groups with the fasting triglyceride concentration (r = 0.83; P = 0.0001). Retinyl palmitate measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction was also significantly greater in NIDDM with HTG, but did not differ significantly between NIDDM with NTG and controls. In NIDDM with HTG, chylomicrons appeared to be cleared at a slower rate, as evidenced by the significantly later intersection of the chylomicron and nonchylomicron retinyl palmitate response curves (13.7 h in HTG NIDDM vs. 8.5 h in NTG NIDDM vs. 7.3 h in controls; P less than 0.01). Although fasting FFA levels were similar in all three groups, the HTG diabetic subjects had a late postprandial surge in FFAs that lasted for up to 14 h. The postprandial FFA elevation in all groups correlated with the fasting triglyceride concentration (r = 0.57; P less than 0.002) and postprandial triglyceride increment (r = 0.80; P = 0.0001). The fasting core triglyceride content of the HDL particles in NIDDM with HTG was significantly elevated compared to those in NIDDM with NTG and controls (21.0% vs. 14.0% vs. 14.1% respectively; P less than 0.05), and this increased proportionately in all groups after the meal at the expense of cholesteryl ester, the increase correlating with total plasma postprandial triglyceride increment (r = 0.51; P less than 0.01). We conclude that moderate fasting hypertriglyceridemia in NIDDM is predictive of a constellation of postprandial changes in lipids and lipoproteins that may potentiate the already unfavorable atherogenic fasting lipid profile in these subjects.

Blood Glucose↗
PubMed1991

Influence of dietary lipids on hepatic mRNA levels of proteins regulating plasma lipoproteins in baboons with high and low levels of large high density lipoproteins.

Selective breeding of baboons has produced families with increased plasma levels of large high density lipoproteins (HDL1) and very low (VLDL) and low (LDL) density lipoproteins when the animals consume a diet enriched in cholesterol and saturated fat. High HDL1 baboons have a slower cholesteryl ester transfer, which may account for the accumulation of HDL1, but not of VLDL and LDL. To investigate the mechanism of accumulation of VLDL + LDL in plasma of the high HDL1 phenotype, we selected eight half-sib pairs of baboons, one member of each pair with high HDL1, the other member with little or no HDL1 on the same high cholesterol, saturated fat diet. Baboons were fed a chow diet and four experimental diets consisting of high and low cholesterol with corn oil, and high and low cholesterol with lard, each for 6 weeks, in a crossover design. Plasma lipids and lipoproteins and hepatic mRNA levels were measured on each diet. HDL1 phenotype, type of dietary fat, and dietary cholesterol affected plasma cholesterol and apolipoprotein (apo) B concentrations, whereas dietary fat alone affected plasma triglyceride and apoA-I concentrations. HDL1 phenotype and dietary cholesterol alone did not influence hepatic mRNA levels, whereas dietary lard, compared to corn oil, significantly increased hepatic apoE mRNA levels and decreased hepatic LDL receptor and HMG-CoA synthase mRNA levels. Hepatic apoA-I message was associated with cholesterol concentration in HDL fractions as well as with apoA-I concentrations in the plasma or HDL. However, hepatic apoB message level was not associated with plasma or LDL apoB levels. Total plasma cholesterol, including HDL, was negatively associated with hepatic LDL receptor and HMG-CoA synthase mRNA levels. However, compared with low HDL1 baboons, high HDL1 baboons had higher concentrations of LDL and HDL cholesterol at the same hepatic mRNA levels. These studies suggest that neither overproduction of apoB from the liver nor decreased hepatic LDL receptor levels cause the accumulation of VLDL and LDL in the plasma of high HDL1 baboons. These studies also show that, in spite of high levels of VLDL + LDL and HDL1, the high HDL1 baboons had higher levels of mRNA for LDL receptor and HMG-CoA synthase. This paradoxical relationship needs further study to understand the pathophysiology of VLDL and LDL accumulation in the plasma of animals with the high HDL1 phenotype.

Animals↗
PubMed1991

Nonlysosomal cytoplasmic degradation.

Several types of cytoplasmic and nuclear inclusions represent stages in the process of non-lysosomal cytoplasmic degradation. Nonlysosomal degradation takes place in regions where cytoplasmic components are trapped and not accessible to primary and secondary lysosomes. Such trapping occurs within the lumina of the nuclear envelope and of endoplasmic reticulum in the form of inverted vesicles, within the nucleus, within mitochondria and within cavities formed by the process of topolysis in neutral lipid droplets. The concept of the process of nonlysosomal degradation permits dynamic interpretation of various inclusions as the concept of the process of focal cytoplasmic degration (autophagy) leads to dynamic interpretation of the lysosome.

Animals↗
PubMed1991

Use of an unsaturated fatty acid auxotroph of Saccharomyces cerevisiae to modify the lipid composition and function of mitochondrial membranes.

KD115 (ol1), an unsaturated fatty acid auxotroph of S. cerevisiae, was grown in a semi-synthetic medium supplemented with 3.3 x 10(-4) M palmitoleic (cis 16:1) or palmitelaidic (trans 16:1) acids. The parent strain S288C was studied as a control. The lipid composition (fatty acids, neutral lipids, and phospholipids), respiratory activity (O2 consumption), and ultrastructure were compared in mutant yeast grown with each unsaturated fatty acid supplement. The fatty acid supplement represented 70-80% of the yeast fatty acids. Yeast grown in trans 16:1 contained more squalene, a higher ratio of phosphatidylethanolamine (PE) to phosphatidylcholine (PC), and had 10-20% of the respiratory activity compared to the same yeast grown in cis 16:1. The mitochondrial morphology of yeast in each growth supplement was notably different. The use of mixtures of cis and trans 16:1 in different proportions revealed that the PE/PC ratio, the squalene content, the respiratory defect, and the mitochondrial morphology were all similarly dependent on the fraction of trans 16:1 in the mixtures. As little as 10-20% of cis 16:1 in the mixture was sufficient to abrogate the physiological effects of trans 16:1 on each of the parameters noted above. The combined effects of high content of trans unsaturated fatty acid and the altered phospholipid composition seem to account for the decrease in lipid fluidity, the defective structure and function of the mitochondrial membrane.

Fatty Acids↗
PubMed1990

Regulation of transcriptional initiation in yeast mitochondria.

We have investigated in vitro transcriptional initiation by purified yeast mitochondrial RNA polymerase using a variety of previously described promoter variants and dinucleotides corresponding to the first two transcript nucleotides. Regardless of the actual nucleotides that occupy the first two transcript positions, the rate of initiation increases with increasing concentrations of the first two ribonucleoside triphosphates up to 125 microM whereas elongation is carried out optimally with less than 10 microM. Under normal in vitro transcription conditions, mitochondrial RNA polymerase only employs the in vitro start site (+1 position), again without regard to the nucleotide at the position. Even with initiator dinucleotide monophosphates as primers, the polymerase is only capable of initiating transcription at this position and one other, i.e. 1 base upstream (-1). Dinucleotides enhance transcription from partially active variant promoters (mutations around the initiation sites -3, -1, +1, +2), suggesting that these mutations reduce transcription by their effects on initiation. In contrast, inactive promoters (-7C, -6G, -4A, and -2A) are not active in the presence of initiating dinucleotide. We suggest that dinucleotides may function in one of three ways: (i) bypassing the energy barrier in forming the first internucleotide bond; (ii) stabilizing the initiation complex; or (iii) accelerating promoter clearance.

Base Sequence↗
PubMed1990

Environmentally induced differential amplification of mitochondrial populations.

Resistance to the drug rutamycin, an inhibitor of mitochondrial ATPase, has been shown to be cytoplasmically inherited in a mouse fibroblast line (TL) on fusion of the cytoplast (enTL) with a nucleated recipient A9 [Lichtor & Getz (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 324-328]. The cytoplasmic hybrid (cybrid) so formed may be readily grown in the presence [CY(+)] or absence [CY(-)] of rutamycin. The ATPase of TL mitochondria is similarly resistant to rutamycin whether grown in the presence or absence of antibiotic. The ATPase of CY(+) mitochondria is resistant to rutamycin, but CY(-) mitochondrial ATPase is sensitive to rutamycin. Nevertheless, CY(-) can be readily grown in rutamycin after a brief lag. The pH optima of mitochondrial ATPase are 8.0 for A9 and CY(-) cells and 7.5 for TL cells, whereas the pH optimum for CY(+) spans the optima of A9 and TL. The TL mitochondrial NADH-cytochrome c reductase is resistant to rotenone, whereas that of A9 mitochondria is sensitive to this agent. CY(-) and CY(+) mitochondria are sensitive and resistant respectively to rotenone. Growth of cybrids in rutamycin for 2 weeks results in a 2-3-fold increase in mitochondrial mass, measured on the basis of electron microscopic morphometry, mitochondrial membrane enzyme assays, mass of cardiolipin, and quantification of mitochondrial DNA. These data suggest that the cybrid harbours two populations of mitochondria and that the proportions of the two populations dramatically influence morphology, growth and mitochondrial phenotype in the cybrid. Selective pressure appears to induce these changes through the differential amplification of mitochondria.

Adenosine Triphosphatases↗
PubMed1990

Postprandial lipoprotein metabolism in normal and obese subjects: comparison after the vitamin A fat-loading test.

Abnormalities in fasting lipid and lipoprotein levels are known to occur in obesity and other hyperinsulinemic states. However, postprandial lipoprotein metabolism has not been studied systematically in obese subjects using sensitive techniques to distinguish between triglyceride-rich lipoprotein particles derived from the intestine and the liver. In the present study the vitamin A fat-loading test was used to label intestinally derived triglyceride-rich lipoprotein particles in the postprandial state. Lipid parameters in seven normolipidemic obese subjects [body mass index, 43.7 +/- 2.81 kg/m2 (mean +/- SEM)] were compared to those in eight matched normal weight controls (body mass index, 23.6 +/- 0.72 kg/m2) during the 24-h period following ingestion of a mixed meal with a high fat content to which vitamin A had been added. Although subjects were selected for normal fasting lipid levels, in the obese group fasting triglycerides were significantly higher (1.35 +/- 0.12 vs. 0.68 +/- 0.08 mmol/L; P less than 0.0005) and high density lipoprotein (HDL) cholesterol was lower (0.94 +/- 0.08 vs. 1.35 +/- 0.11 mmol/L; P less than 0.01). The obese subjects had a greater postprandial triglyceride response to the test meal (P less than 0.05). The cumulative increment in total plasma triglycerides was 3.35-fold greater in obese than control subjects, while that of retinyl ester was only 1.63-fold greater, suggesting that a significant portion of the postprandial triglyceride response is due to endogenous hepatic lipoproteins. Postprandial plasma triglyceride and retinyl ester increment correlated with basal triglycerides (r = 0.72; P less than 0.005 and r = 0.57; P less than 0.03, respectively) and negatively with fasting HDL (r = -0.51; P less than 0.05 and r = -0.60; P less than 0.02, respectively). In the obese, the HDL triglyceride content increased maximally 4 h postprandially (4.1% to 6.1%; P less than 0.005) and phospholipid at 12 h (25.8% to 28.7%; P less than 0.05), with lower cholesteryl ester (21.1% to 17.5%; P less than 0.002) at 8 h, reflecting exchange of surface and core lipids with triglyceride-rich particles after the meal. In obese and control subjects the magnitude of HDL triglyceride enrichment after the meal correlated positively with the postprandial triglyceride increment (r = 0.74; P less than 0.007) and negatively with the fasting HDL cholesterol concentration (r = -0.80; P = 0.002). We conclude that even normolipidemic obese subjects have greater postprandial lipemia and triglyceride enrichment of HDL after ingestion of a high fat meal.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

An overview of atherosclerosis: a look to the future.

This overview briefly summarizes the cellular pathobiology of experimental atherosclerosis and is then followed by a consideration of how 3 major risk factors interact with the hypothesized pathogenetic process. First, since hemodynamics and blood flow influence the localization of atherosclerotic plaques, possible mechanisms and directions of research are considered. Secondly, the recent hypothesis relating the oxidation of LDL to several of the early processes of atherogenesis is briefly discussed in view of the fact that hyperlipidemia is a major risk factor. The possibility that subsets of LDL and lipoproteins other than LDL might be involved is also discussed. Family history is the last of the 3 contributors to atherosclerosis reviewed and some prototypes of gene abnormalities are considered. Finally, the needs and prospects of future research are summarized.

Animals↗
PubMed1990

Impaired plasma cholesteryl ester transfer with accumulation of larger high density lipoproteins in some families of baboons (Papio sp.).

Baboons from some families have a higher concentration of plasma high density lipoproteins (HDL) on a chow diet and accumulate large HDL (HDL1) when challenged with a high cholesterol and high saturated fat (HCHF) diet. HDL1 from high HDL1 animals contained more (1.5-fold) cholesteryl ester than HDL (HDL2 + HDL3) from high or low HDL1 animals. HDL from high HDL1 baboons had lower triglyceride content than that from low HDL1 baboons. HDL3 or HDL labeled with [3H]cholesteryl linoleate was incubated with entire lipoprotein fraction (d less than 1.21 g/ml) or very low density lipoprotein + low density lipoprotein (VLDL + LDL) (d less than 1.045 g/ml) and with lipoprotein-deficient serum (LPDS), and the radioactive cholesteryl ester and mass floating at d 1.045 g/ml (VLDL + LDL) after the incubation was measured. The transfer of cholesteryl esters from either HDL or HDL3, prepared from plasma of high HDL1 animals fed chow or the HCHF diet, was slower than the transfer from either HDL or HDL3 of low HDL1 animals, regardless of the source of transfer activity or the ratio of LDL:HDL-protein used in the assay. Addition of HDL from high HDL1 baboons into an assay mixture of plasma components from low HDL1 baboons decreased the transfer of cholesteryl ester radioactivity and mass from HDL to VLDL and LDL. In addition to HDL, a fraction of intermediate density lipoprotein (IDL) and denser HDL were also effective in inhibiting the transfer. These observations suggest that accumulation of HDL1 in high HDL1 baboons fed an HCHF diet is associated with a slower transfer of cholesteryl esters from HDL to LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Rat granulosa cell apolipoprotein E secretion. Regulation by cell cholesterol.

We have demonstrated previously that cultured rat ovarian granulosa cells synthesize and secrete apoE, and this production of apoE is increased by agents that stimulate protein kinase A (cyclic AMP-dependent enzyme) (for example, cholera toxin) and protein kinase C (Ca2+/phospholipid-dependent enzyme) (for example, 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester). In the studies presented in this report, we have examined the effect of changes in cell cholesterol synthesis on the production of apoE by rat ovarian granulosa cells. Mevinolin, an inhibitor of hydroxymethylglutaryl (HMG)-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), and 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, an inhibitor of squalene cyclization, both attenuate the cholera toxin or 12-O-tetradecanoylphorbol-13-acetate stimulation of granulosa cell apoE secretion and apoE mRNA content in a dose-responsive manner. The inhibitory effect of mevinolin is reversed by the concomitant administration of mevalolactone, which provides the cells with the product of the reaction catalyzed by HMG-CoA reductase. Steroidogenesis per se has no effect on apoE production. Aminoglutethimide, which blocks the rate-limiting step in steroidogenesis, has no effect on apoE or apoE mRNA. The data indicate that products of HMG-CoA reductase (isoprenes, cholesterol and/or cholesterol metabolites) are required along with stimulators of protein kinases A and C, to regulate ovarian granulosa cell apoE production.

Aminoglutethimide↗
PubMed1989

Mechanism of the growth-related activation of the low density lipoprotein receptor pathway.

Growth activation of quiescent cells leads to enhanced low density lipoprotein (LDL) receptor expression at the cell surface. To determine the basis for this stimulated receptor activity, we measured LDL receptor activity, changes in receptor protein mass, and mRNA abundance in quiescent and growth-activated cultured human skin fibroblasts. Growth activation, using insulin or platelet-derived growth factor, led to dose-dependent increases in cellular LDL receptor mRNA level (average 5.2-fold increase at 10 ng/ml platelet-derived growth factor, 4.1-fold increase at 58 ng/ml insulin) and cell surface expression (average 3.5-fold increase at 10 ng/ml platelet-derived growth factor, 2.5-fold increase at 58 ng/ml insulin). Increased LDL receptor mRNA levels could be detected as early as 2 h after addition of growth factor (3.2-fold), whereas increased levels of LDL receptor binding and mass were not detected until after 4-8 h. Growth activation led to induction of LDL receptor gene transcription, led to induction of LDL receptor gene transcription, and the increase of LDL receptor mRNA produced by addition of growth factor was completely prevented by actinomycin D. These observations indicate that growth-related activation of the LDL receptor pathway is accounted for, primarily, by growth-activated enhancement of LDL receptor gene transcription.

Cell Division↗