Biomedical subjects

T Mazzone

Publications and source records attributed to T Mazzone.

At least 55 records · Page 3Linked to original sources

PubMed1992

C4 serum levels in newborns of diabetic mothers: relationship with metabolic assessment during pregnancy.

Serum levels of C4 complement factor are lower in diabetic patients: it is supposed that this finding is related to genetic inheritance factors of diabetes. The purpose is to compare C4 levels in newborns of diabetic mothers with maternal metabolic control during pregnancy. The results suggest that metabolic control could influence the expression of genetic factors of diabetes; in fact C4 serum levels in newborns are significantly higher (p < 0.01) than controls, but not different from those observed in large newborns of non diabetic mothers.

Complement C4↗

PubMed1991

Dissociated regulation of macrophage LDL receptor and apolipoprotein E gene expression by sterol.

The control of apoE gene expression by sterols and the relationship between regulation of the apoE and low density lipoprotein (LDL) receptor genes were investigated in a human macrophage line. Incubation of THP1 cells in either LDL or acetylated LDL increased apoE mRNA levels 4- to 15-fold. In addition, the cellular abundance of these two mRNA species (apoE and LDL receptor) was inversely regulated by cellular cholesterol content over an identical dose-response relationship. Regulation of the LDL receptor and apoE genes could, however, be temporally dissociated in response to the accumulation or removal of lipoprotein-derived (exogenous) cholesterol and in response to perturbation of endogenous cellular cholesterol biosynthesis. In addition, we observed that the apoE gene responded more promptly to 25-hydroxycholesterol than to exogenous cholesterol. These data support the concept that the apoE gene be considered among the family of genes sensitively regulated by cellular sterol balance but suggest that the molecular mechanism accounting for the modulation of the LDL receptor and apoE genes are distinct, with the relationship between cell sterol balance and apoE gene regulation being more complex.

Apolipoproteins E↗

PubMed1990

Growth-related modulation of human skin fibroblast cholesterol distribution and metabolism.

The relationship between cell growth state and the metabolism and distribution of cellular cholesterol was studied in human skin fibroblasts. Cells made quiescent by serum starvation maintained a smaller fraction of total free cholesterol in a pool susceptible to oxidation by added cholesterol oxidase compared to growing cells. The growth-related differences in the distribution of free cholesterol were magnified in cells which were preincubated in low-density lipoprotein. These latter cells hydrolyzed cholesteryl ester which had accumulated in the presence of LDL, resulting in an increased level of cellular free cholesterol after growth activation. By preincubating cells in [3H]cholesterol linoleate-labeled LDL, it could be demonstrated that activation of cell growth facilitated the appearance of LDL-derived cholesterol in a pool accessible to cholesterol oxidase. These studies suggest that onset of growth in fibroblasts leads to a redistribution of free cholesterol from intracellular to plasma membrane compartments. Furthermore, activation of cell growth in cholesterol loaded cells leads to the net conversion of cholesteryl ester to free cholesterol and most of the latter is in the plasma membrane.

Cell Division↗

PubMed1990

Relation of growth- and sterol-related regulatory pathways for low density lipoprotein receptor gene expression.

The relationship between growth- and sterol-related regulation of low density lipoprotein (LDL) receptor gene expression was examined in human skin fibroblasts. Platelet-derived growth factor (PDGF) and high density lipoprotein (HDL3) each produced increased cellular LDL protein and mRNA levels. However, HDL, when added with PDGF or insulin produced no additional effect. Coincubations with 25-hydroxycholesterol markedly attenuated fibroblast LDL receptor protein and mRNA response to growth activation. Acute transfection experiments using sterol-responsive elements of the LDL receptor gene indicated that these elements are also responsive to growth activation with PDGF. These data indicate that alteration of cellular sterol balance or metabolism leading to release of end product repression contributes to growth-related stimulation of LDL receptor gene expression.

Base Sequence↗

PubMed1989

Inhibitors of translation induce low density lipoprotein receptor gene expression in human skin fibroblasts.

The effect of protein synthesis inhibitors on low density lipoprotein (LDL) receptor gene expression was examined in human skin fibroblasts. Incubations in cycloheximide led to a marked increase in LDL receptor mRNA abundance as detected by Northern or slot-blot hybridization analyses. Incubation in puromycin had a similar effect. After the addition of cycloheximide, induction of LDL receptor mRNA levels was rapid (peaking between 2 and 3 h) and transient (falling to control levels by 24 h). This incubation could not be accounted for by the modest stabilization of mature LDL receptor mRNA species produced by cycloheximide and was completely abolished by concurrent addition of actinomycin D. Nuclear run-off transcription assays demonstrated increased LDL receptor gene transcription after 20-min incubations in cycloheximide. Induction of LDL receptor mRNA by cycloheximide was partially resistant to sterol suppression and was at least additive with induction produced by growth activation of cells using platelet-derived growth factors. These results indicate that inhibition of protein synthesis leads to rapid stimulation of LDL receptor gene transcription by a mechanism which is partially resistant to sterol suppression. We further conclude that early stimulation of LDL receptor gene expression associated with growth-activation of quiescent cells is independent of new protein synthesis.

Cells, Cultured↗

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↗

PubMed1989

Effects of feeding fish oil on the properties of lipoproteins isolated from rhesus monkeys consuming an atherogenic diet.

This study examined plasma lipids and lipoproteins of rhesus monkeys fed fish oil incorporated into a highly atherogenic diet containing saturated fat and cholesterol. The animals were fed diets containing 2% cholesterol and either 25% coconut oil (group I), 25% fish oil/coconut oil (1:1; group II), or 25% fish oil/coconut oil (3:1; group III) for 12 months (n = 8/group). Adding menhaden fish oil to the diet increased plasma eicosapentaenoic acid and docosahexaenoic acid and decreased plasma linoleic acid in animals fed the fish oil containing diets. Plasma concentrations of all lipoprotein fractions were decreased in the fish oil groups. VLDL isolated from group I animals exhibited beta-mobility on agarose gels but the VLDL from groups II and III animals did not. The group I VLDL was more highly enriched in cholesteryl ester than was VLDL from groups II and III. Group I LDL had a small but significant increase in cholesteryl ester content compared to group III LDL. No differences in HDL composition were observed in the 3 groups. At least 6 times less apo E was recovered in VLDL, IDL, and LDL from group III animals than from group I animals. Assuming 1 molecule of apo B per lipoprotein particle, there were 50% fewer VLDL, IDL, and LDL particles in group III than in group I animals. Group III also had significantly lower molar ratios of apo E/apo B in VLDL, IDL, and LDL than did group I animals. When VLDL from all 3 groups were incubated with J774 macrophages at equal protein concentrations, only the VLDL from the group I animals stimulated cholesterol esterification. Thus, introducing fish oil into an atherogenic diet reduced the number of VLDL, IDL and LDL particles in plasma by as much as 50%, reduced the cholesteryl ester content of the circulating lipoprotein, and reduced the ability of the VLDL to stimulate cholesterol esterification in macrophages.

Animals↗

PubMed1989

Regulation of macrophage apolipoprotein E gene expression by cholesterol.

The relationship between macrophage cholesterol content and apolipoprotein E (apoE) gene expression was investigated in cultured mouse peritoneal macrophages. Acetylated low density lipoprotein (ALDL) at 25 micrograms/ml led to increased macrophage messenger RNA abundance as detected by Northern blot hybridization. Incubation in a range of ALDL concentrations (0-100 microgram/ml) led to graded increases in macrophage free and esterified cholesterol, and apoE mRNA detected by slot blot hybridization. After a 2-h pulse of ALDL, with or without acyl-CoA:cholesterol acyltransferase inhibition, increased apoE mRNA was not detected until after 6 h. Removal of cholesterol from upregulated macrophages, using human high density lipoprotein, resulted in a return of apoE mRNA levels toward baseline. Nuclear run-off transcription assays demonstrated increased apoE gene transcription in macrophages incubated with ALDL. It is concluded that: a) previously reported changes in macrophage apoE content and secretion after cholesterol enrichment or depletion can be attributed to changes in apoE mRNA levels; and b) cholesterol-induced changes in apoE mRNA are associated with increased apoE gene transcription.

Animals↗

PubMed1989

Synchronous occurrence of parathyroid carcinoma and adenoma in an elderly woman.

The simultaneous occurrence of parathyroid carcinoma and other pathologic conditions of the parathyroid on a sporadic basis is extremely rare. Parathyroid exploration in an otherwise healthy 78-year-old woman with no underlying risk factors revealed synchronous right upper parathyroid adenoma and left upper parathyroid carcinoma. The patient's modest hypercalcemia (11.5 to 12.3 mg/dl) was seemingly at variance with remarkable parathormone elevations of 30 to 70 times normal.

Adenocarcinoma↗

PubMed1988

Atherosclerosis and apoprotein E. An enigmatic relationship.

In this article, we consider the role of apoprotein E in lipoprotein metabolism and especially in the metabolism of potentially atherogenic lipoproteins. Particular consideration has been given to three features of apoprotein E involvement in lipid cell interactions. Evidence implicating free cholesterol as a mediator of apoprotein E biosynthesis in cholesterol-loaded macrophages is presented. Experiments pointing to apoprotein E as the ligand promoting the interaction of beta-very-low-density lipoprotein (beta-VLDL) with macrophages are summarized. Finally, we describe the influence of fat and cholesterol fed to rhesus monkeys and baboons on the generation of hepatogenous (from isolated liver perfusates) VLDL enriched in cholesterol ester and apoprotein E. These hepatic VLDLs, none of which exhibits beta-electrophoretic mobility, promote cholesterol esterification in macrophages in proportion to their apoprotein E content. The complex role of apoprotein E in the genesis and reversal of atherosclerosis is briefly discussed.

Animals↗

PubMed1988

Hepatic perfusate very low density lipoproteins obtained from fat-fed nonhuman primates stimulate cholesterol esterification in macrophages.

The livers of both baboons and rhesus monkeys fed a high fat, high cholesterol diet secreted very low density lipoproteins (VLDL) that were enriched in cholesteryl ester and apoe as compared to VLDL secreted by the livers of chow-fed animals. Stimulation of macrophage cholesterol esterification by the experimental VLDL was compared to that produced by the standard beta-VLDL obtained from the plasma of a rhesus monkey fed 25% coconut oil plus 2% cholesterol. This standard beta-VLDL stimulated 7- to 10-fold more esterification than did the bovine albumin control. Hepatic VLDL from fat-fed animals stimulated esterification in J774 macrophages 50 to 150% as well as did the standard beta-VLDL, even though hepatic VLDL did not display beta electrophoretic mobility on agarose gel electrophoresis. Plasma VLDL from lard-fed baboons did not exhibit beta electrophoretic mobility but did stimulate esterification in macrophages. Baboons were divided into high and low responders based on the change in plasma cholesterol levels in response to a high fat, high cholesterol diet. Both plasma and hepatic VLDL from high responders stimulated cholesterol esterification, whereas hepatic VLDL obtained from low responders or chow-fed baboons did not stimulate cholesterol esterification in macrophages. There was a strong positive correlation (r = 0.866) between the number of apoE molecules per VLDL particle in VLDL obtained from chow-fed, lard-fed, or coconut oil-fed primates and the rate of cholesterol esterification in macrophages. Our results show that hepatic perfusate VLDL obtained from fat- and cholesterol-fed primates have compositional and functional properties usually ascribed to circulating beta-VLDL, without displaying beta mobility, and indicate that the liver may be an important source of atherogenic lipoproteins.

Animals↗

PubMed1987

Macrophage free cholesterol content regulates apolipoprotein E synthesis.

The relationship between macrophage cholesterol content and apolipoprotein E (apoE) synthesis was studied in mouse peritoneal macrophages. Incubations in acetylated low density lipoprotein led to a concentration-dependent increase in macrophage free and esterified cholesterol content and apoE synthesis. Enhanced apoE production reflected increased apoE mRNA abundance in cholesterol-enriched cells. Including an inhibitor of acyl-CoA:cholesterol acyltransferase in incubations with acetylated low density lipoprotein did not diminish the apoE response, suggesting that increased macrophage free cholesterol content was responsible for enhancing apoE production. Incubations in 25-OH cholesterol also produced a dose-dependent stimulation of macrophage apoE synthesis. Removing free cholesterol from cells using high density lipoprotein returned apoE synthetic rates toward base line. Macrophage lysate apoE and medium apoE levels changed in parallel during cholesterol loading and efflux indicating that regulation of apoE by free cholesterol was not primarily at the level of secretion. It is concluded that (a) cholesterol enrichment of macrophages increases apoE mRNA abundance and stimulates apoE synthesis and secretion; (b) neither cholesterol esterification nor cholesteryl ester accumulation are required for increased apoE production.

Apolipoproteins E↗

PubMed1987

Apoprotein E mediates the interaction of beta-VLDL with macrophages.

beta-Very low density lipoproteins (beta-VLDL) isolated from cholesterol-fed rhesus monkeys stimulated cholesteryl ester synthesis and accumulation in mouse peritoneal macrophages. The apoprotein specificity and requirement for the cell surface uptake of beta-VLDL was investigated by treating the beta-VLDL with trypsin (beta-VLDL (T], incubating the beta-VLDL (T) with other lipoproteins or apoproteins, reisolating the beta-VLDL (T) and measuring its biological activity which, for this study, is defined as the ability of the lipoprotein to stimulate cholesterol esterification in the macrophages. Trypsin treatment of beta-VLDL abolished its biological activity. Apoprotein analysis of the beta-VLDL (T) demonstrated the absence of intact apoproteins B-100, B-48, and E. The J774 macrophage-like cell line and mouse peritoneal macrophages responded similarly with respect to cholesterol esterification following incubation with inactive and treated beta-VLDL. The J774 macrophage-like cell line was used to establish the conditions necessary for the restoration of biologic activity to the trypsinized beta-VLDL. The loss of biological activity of beta-VLDL (T) could be reversed by restoring apoprotein E-containing LDL from hyperlipemic monkeys or purified apoprotein E. Apoprotein A-I had no such effect. The restored biological activity of the beta-VLDL (T) was proportional to the amount of apoprotein E acquired by the lipoprotein. beta-VLDL particles composed of apoprotein E and either intact or degraded apoprotein B-100 had comparable biological activity. Thus, intact apoprotein E, without intact apoprotein B, is a sufficient mediator for the biological activity and metabolism of beta-VLDL by macrophages and plays a major role in receptor-lipoprotein interaction.

Animals↗

PubMed1986

Early kinetics of human macrophage apolipoprotein E synthesis and incorporation of carbohydrate precursors.

Apolipoprotein E was detected in human macrophage lysates after 4-120-min pulses with [35S]methionine. Significant levels of apolipoprotein E were not found in the media until 120 min. Incorporation of N-[3H]acetylmannosamine, a sialic acid precursor, into apolipoprotein E was measurable after 120 min, whereas no [3H]mannose incorporation could be observed. These methods will be useful for examining the regulation of apolipoprotein E secretion and carbohydrate processing.

Acetylglucosaminidase↗

PubMed1986

Dexamethasone modulates lipoprotein metabolism in cultured human monocyte-derived macrophages. Stimulation of scavenger receptor activity.

Human monocyte-derived macrophages (HMM) play a key role in the formation of atherosclerotic plaques by accumulating cholesteryl ester (CE) to become foam cells. HMM have receptors for native low density lipoprotein (LDL) and acetylated-LDL (ALDL), and uptake of ALDL can promote substantial cellular CE accumulation. Furthermore, macrophages specifically and saturably bind glucocorticoids, which in turn modulate numerous macrophage functions. Preincubating HMM in dexamethasone-inhibited LDL degradation (230 +/- 12 vs. 515 +/- 21 ng/mg cell protein X 18 h, P less than 0.001) but stimulated ALDL degradation (5.3 +/- 0.5 vs. 2.5 +/- 0.3 micrograms/mg X 18 h, P less than 0.01). These effects were time- and dose-dependent, occurring maximally by 24 h and with 2.5 X 10(-8) M dexamethasone. Dexamethasone increased the maximum velocity for ALDL degradation (16.2 vs. 12.0 micrograms/mg X 18 h, P less than 0.01) without changing the apparent Michaelis constant. Progesterone, 11 alpha-epicortisol, and 17 alpha-OH progesterone (a competitive antagonist of the glucocorticoid receptor) had no effect on HMM ALDL degradation, but 17 alpha-OH progesterone abolished the stimulatory action of dexamethasone. In he presence of ALDL, incorporation of [14C]oleic acid into CE was enhanced over fourfold by dexamethasone (4015 +/- 586 vs. 943 +/- 91 cpm/mg X 2 h, P less than 0.01), and HMM incubated with ALDL and dexamethasone accumulated more free cholesterol (34.6 +/- 1.9 vs. 26.2 +/- 0.8 micrograms/mg, P less than 0.02) and CE (32.8 +/- 2.3 vs. 14.8 +/- 0.8 micrograms/mg, P less than 0.002) than did macrophages without dexamethasone. In cultured human umbilical vein endothelial cells, dexamethasone did not change ALDL degradation, but reduced LDL degradation by 30% (P less than 0.001). In summary, dexamethasone inhibits LDL receptor activity by both macrophages and endothelial cells, but stimulates ALDL receptor activity only in macrophages. These observations provide evidence for the regulation of macrophage endocytic receptors by glucocorticoid hormones.

17-alpha-Hydroxyprogesterone↗

PubMed1984

In vivo stimulation of low-density lipoprotein degradation by insulin.

The effect of insulin on low-density lipoprotein (LDL) metabolism in vivo was evaluated using the euglycemic insulin clamp technique. In seven subjects, mononuclear cells isolated after a 4-h insulin infusion degraded more 125I-labeled LDL than cells isolated after a saline infusion in six control subjects. In addition, insulin caused the accelerated disappearance of 125I-labeled LDL from plasma in subjects previously injected with autologous 125I-LDL. Infusion of saline had no such effect. These data suggest that insulin, in vivo, stimulates LDL catabolism and could thereby influence LDL cholesterol levels. Insulin-induced stimulation of LDL catabolism could account for the reduction of LDL-cholesterol levels observed in intensively treated type I diabetic patients.

Adult↗

PubMed1983

Lymphocytic hypophysitis. Associated with antiparietal cell antibodies and vitamin B12 deficiency.

Lymphocytic hypophysitis has been recognized as a distinct clinicopathologic entity. It is a cause of hypopituitarism in the postpartum period and is believed to have an autoimmune pathogenesis. We treated a patient with lymphocytic hypophysitis with two unique features. First, this patient had had a prolactin level of 101 ng/mL (normal, 0 to 25 ng/mL). To our knowledge, this degree of elevation has not been previously reported and is a level that might cause confusion with prolactin-secreting pituitary adenomas. Second, this patient had positive titers for antiparietal cell antibodies in conjunction with a low vitamin B12 level and anemia. To our knowledge, this is the first report of a clinically important autoantibody to extrapituitary tissue in a living patient with lymphocytic hypophysitis.

Antibodies↗

PubMed1983

Human arterial wall cells secrete factors that are chemotactic for monocytes.

Macrophages and arterial smooth muscle cells comprise the cellular components of the atherosclerotic plaque. The vessel wall accumulation of macrophages occurs by a process of increased circulating monocyte migration into the vessel wall. In these studies it is demonstrated that human macrophages and arterial smooth muscle cells in culture secrete potent chemotactic factors for freshly isolated human monocytes. In contrast, human fibroblast-conditioned medium has no chemotactic activity. The effect of macrophage-conditioned medium is a function of macrophage differentiation and can be potentiated by macrophage activation. These results suggest that secretory products of human macrophages and arterial smooth muscle cells may be important stimuli for increased monocyte migration into the vessel wall in vivo.

Arteries↗