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Paola Moreno, Bernardo Nuche-Berenguer, Irene Gutiérrez-Rojas, Alicia Acitores, Verónica Sancho, Isabel Valverde, Nieves González and María L Villanueva-Peñacarrillo

-1 (GLP-1 or GCG as listed in the HUGO database), an incretin hormone with anti-diabetic properties, exerts insulin-like effects upon glucose transport (GT) and metabolism in the liver, skeletal muscle, and fat of humans and rats ( Valverde et al

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L. A. Berry and P. Skett

ABSTRACT

The effects of various concentrations of cyclic AMP (cAMP) on the metabolism of androst-4-ene-3,17-dione were examined in electropermeabilized rat hepatocytes. cAMP had a biphasic effect on hepatic steroid metabolism which was dependent upon [ill] concentration and time. At low concentrations (50 μm) early (1 h) inhibitory effects predominated, whereas at higher concentrations (5 mm) later (2–3 h) stimulatory effects were seen. The use of selective protein kinase inhibitors indicated that all the effects of cAMP were mediated through activation of protein kinase A, but that the inhibitory response also involved activation of protein kinase C. The stimulatory effect was blocked by cycloheximide, indicating that protein synthesis is necessary for this response. These findings help to elucidate the mechanisms by which hormones and other compounds may give their effects on hepatic steroid metabolism and indicate a possibly novel interaction of cAMP and protein kinase C.

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C Svensson

ABSTRACT

This study was undertaken to investigate the effects of growth hormone (GH) on the in vitro maturation of the metabolism of fetal rat islets. For this purpose fetal islets were obtained from 21-day-old fetuses by mild collagenase digestion of the pancreas and cultured in RPMI 1640 supplemented with 10% fetal calf serum. After one day the medium was changed and supplemented with 1% fetal calf serum with or without GH (1 μg/ml, human recombinant) and the islets cultured for another two days. Islets were then studied with regard to insulin secretion, (pro)insulin and total protein biosynthesis, glucose utilization and oxidation, thymidine incorporation, insulin and DNA contents and the contents of mRNAs for either insulin, adenine nucleotide translocator or cytochrome b. In addition, the activities of glucose phosphorylating enzymes and succinate-cytochrome c reductase were measured. Islets treated with GH showed increased insulin secretion in response to glucose, increased rates of glucose oxidation and utilization, increased thymidine incorporation and increased activities of succinate cytochrome c reductase and glucose phosphorylation at high glucose concentrations. There were, however, no changes in (pro)insulin and total protein biosynthesis, contents of insulin and DNA or the contents of any of the mRNAs. These combined data show that fetal β-cells are sensitive to growth hormone with respect to glucose metabolism, insulin release and DNA replication. The increased rates of islet glucose phosphorylation may reflect glucokinase activity and explain part of the increased insulin responsiveness to glucose of the fetal rat β-cell. These observations suggest that GH is of physiological significance for the maturation of the fetal β-cell.

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T.H. Jones, B. L. Brown and P. R. M. Dobson

ABSTRACT

Bradykinin stimulated prolactin secretion from monolayer cultures of rat anterior pituitary cells, the stimulation being greater from the cells of male rats. This stimulated secretion was accompanied by a rise in total inositol phosphate accumulation, suggesting that the action of bradykinin is mediated by phosphoinositide hydrolysis. The increase in inositol phosphate accumulation was biphasic; a further sharp rise occurred when the concentration of bradykinin exceeded 1 μmol/l. This may indicate that bradykinin acts on other cell types in the pituitary gland. Bradykinin had no effect on growth hormone secretion from cells of normal pituitary glands, or on prolactin secretion and phosphoinositide metabolism in GH3 rat pituitary tumour cells. Bradykinin receptor antagonists (both B1 and B2) had no effect on either bradykinin-stimulated inositol phosphate accumulation or prolactin secretion. Kallikreins, the enzymes responsible for the generation of kinins, are known to be present in the adenohypophysis. Therefore, the results presented here would suggest that kinins may have a role as paracrine agents in the pituitary gland.

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Bolander FF Jr

In a previous study, the envelope protein (gp52) of the mouse mammary tumour virus (MMTV) was shown to facilitate mammary gland differentiation by increasing prolactin (PRL) receptors via increased receptor synthesis and via the redistribution of existing receptors from an internal pool. In this study, receptors for other hormones known to affect mammary gland metabolism were investigated. Epidermal growth factor (EGF) stimulates mammary epithelial growth and inhibits differentiation; its receptor is rapidly and dramatically down-regulated by gp52. This is accomplished by its internalization and by decreasing its half-life from 27 h to 2.4 h. Surprisingly, it also increased EGF receptor synthesis, although this effect was not great enough to overcome receptor down-regulation. In contrast, gp52 did not affect the distribution, half-life or synthesis of the insulin receptor. These results demonstrate that MMTV can enhance mammary differentiation by coordinately regulating several hormone receptors: specifically, it can increase the number of receptors for PRL, a differentiative hormone, while decreasing the number of receptors for EGF, a growth/anti-differentiative hormone.

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Richard C Lindsey, Charles H Rundle and Subburaman Mohan

repair. Interactions between IGF and EFN–EPH signaling There is now substantial evidence in the literature to suggest that interactions between chondrocytes, osteoblasts and osteoclasts are important in the regulation of bone metabolism. In

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Patrizia Agretti, Giuseppina De Marco, Laura Russo, Alessandro Saba, Andrea Raffaelli, Maja Marchini, Grazia Chiellini, Lucia Grasso, Aldo Pinchera, Paolo Vitti, Thomas S Scanlan, Riccardo Zucchi and Massimo Tonacchera

nuclear TH receptors controlling normal vertebrate development, growth, and metabolism ( Yen 2001 ). T 3 -modulated transcription of target genes via activation of TH nuclear receptors is a slow process that requires hours or days. In addition to the

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F. M. Ng, N. A. Adamafio and J. E. Graystone

ABSTRACT

The effects of two preparations of highly purified human GH (hGH) on lipid metabolism were studied in the GH-deficient little mouse (50–60 days old). Marked decreases in incorporation of [14C]glucose into fatty acid and in the activity of acetyl-CoA carboxylase in the epididymal fat pads were observed after i.p. injection of hGH at a dose of 1·0μg/g body weight or after continuous infusion of hGH by osmotic minipump. The rate of glucose incorporation into fatty acid decreased from 107·0 ± 27·6 (s.e.m.) to 38·1 ± 19·6 μmol/g tissue per h after a single injection of hGH and from 174·1±28·5 to 56·3±20·3 μmol/g tissue per h after continuous infusion of hGH for 2 days. Activity of the lipogenic enzyme acetyl-CoA carboxylase was also reduced by more than 50% in the epididymal fat pad from hGH-treated mice in comparison with the corresponding control animals. Incubation of isolated fat pads with hGH (0·1 μg/ml) revealed similar inhibitory effects of the hormone on fatty acid synthesis and acetyl-CoA carboxylase activity. No lipolytic effect of hGH was found as determined by the rate of glycerol release from epididymal fat pads of little mice following hormone treatment in vivo or in vitro. The results lend strong support to the conclusion that GH inhibits lipogenesis but has no effect on lipolysis in adipose tissues, and indicate that the physiological role of GH in lipid metabolism is concerned mainly with the regulation of anabolic rather than catabolic processes.

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JA Vendrell, F Magnino, E Danis, MJ Duchesne, S Pinloche, M Pons, D Birnbaum, C Nguyen, C Theillet and PA Cohen

We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.

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M. E. Hayes, D. Bayley and E. B. Mawer

ABSTRACT

Regulation of the metabolism of [3H]25-hydroxyvitamin D3 ([3H]25-(OH)D3) in vitro to material with the characteristics of [3H]24,25-dihydroxyvitamin D3 ([3H]24,25-(OH)2D3) has been studied in the human promyelocytic cell line HL60. Synthesis of 24,25-(OH)2D3 was induced in a dose-dependent manner in cells pretreated with 0·1–100 nm 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) for 4 days. This treatment also inhibited cell proliferation and stimulated differentiation to a macrophage phenotype that was characterized by staining for non-specific esterase (NSE) activity. The ability to synthesize [3H]24,25-(OH)2D3 from [3H]25-(OH)D3 and the expression of NSE activity both responded to changes in concentration of 1α,25-(OH)2D3 in the culture medium in a parallel manner. Synthesis of [3H]24,25-(OH)2D3 was linear when the incubation time was between 1 and 8 h and the cell number between 1 and 12×106 cells/incubation. The optimum substrate concentration for its synthesis was 125 nm, giving an apparent Michaelis constant of 360 nm. The identity of the [3H]24,25-(OH)2D3 synthesized by these cells was confirmed by co-chromatography with authentic 24,25-(OH)2D3 on normal-phase and reverse-phase high-performance liquid chromatography systems and by its reaction to sodium-m-periodate. Cells that had been exposed to 100 nm 1α,25-(OH)2D3 for 4 days synthesized 2·17±0·07 (s.e.m.) pmol 24,25-(OH)2D3/106 cells per h. This synthesis was inhibited in a dose-dependent manner over a concentration range of 0·01–1 μm by the drug ketoconazole, an antimycotic imidazole which is a known inhibitor of certain cytochrome P-450 enzyme systems, suggesting that the HL60 25-(OH)D3-24-hydroxylase is also a P-450-dependent enzyme system.