The interrelationship between and the regulation of hepatic growth hormone receptors and circulating GH binding protein in the pig

1992 ◽  
Vol 126 (2) ◽  
pp. 155-161 ◽  
Author(s):  
Geoffrey R Ambler ◽  
Bernhard H Breier ◽  
Andrzej Surus ◽  
Hugh T Blair ◽  
Stuart N McCutcheon ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Hormone Receptors ◽  
Binding Capacity ◽  
Binding Protein ◽  
Somatic Growth ◽  
Gh Receptor ◽  
Age Related ◽  
Igf I ◽  
Serum Gh

We evaluated the interrelationship between, and regulation of, the hepatic growth hormone receptor and serum GH binding protein (GH BP) in pigs treated with recombinant porcine growth hormone (rpGH). Infant and pubertal male pigs (N = 5 per group) received either rpGH 0.15 mg/kg daily or diluent intramuscularly for 12 days. Somatic growth, serum IGF-I and GH BP and [125I]bovine GH (bGH) binding to MgCl2-treated hepatic membrane homogenates were examined. Marked age-related increases were seen in serum GH BP (p<0.001) and [125I]bGH binding to hepatic membranes (p<0.001). GH BP was increased in rpGH treated animals (p = 0.03), from 13.8±1.2 (mean±1 x sem) (controls) to 17.8±2.0% in infants, and from 35.2±2.6 (controls) to 41.8±3.4% in pubertal animals. [125I]bGH binding to hepatic membranes was also increased by rpGH treatment (p<0.05), from 7.0±1.6 (controls) to 15.4±3.6% in infants and from 53.7±7.1 (controls) to 65.1±11.8% in pubertal animals. No significant interaction between age and treatment was seen. Overall, serum GH BP correlated significantly with [125I]bGH membrane capacity (r=0.82, p<0.001), with a correlation of r= 0.83 in the infant animals but no significant correlation in the pubertal animals considered alone (r=0.13). Serum IGF-I correlated significantly with serum GH BP (r=0.93, p<0.001) and [125]bGH membrane binding capacity (r = 0.91, p< 0.001). These observations suggest that serum GH BP levels reflect major changes of hepatic GH receptor status. In addition, the present study demonstrates that the hepatic GH receptor can be induced by GH in the infant pig, despite a developmentally low GH receptor population at this age, suggesting potential efficacy of GH at earlier ages than generally considered.

scholarly journals Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

2000 ◽  
Vol 167 (2) ◽  
pp. 295-303 ◽  
Author(s):  
JW van Neck ◽  
NF Dits ◽  
V Cingel ◽  
IA Hoppenbrouwers ◽  
SL Drop ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Binding Protein ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Gh Receptor ◽  
Igf I ◽  
Igfbp 3

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

scholarly journals Growth Hormone Receptor Antagonism Prevents Early Renal in Nonobese Diabetic Mice

1999 ◽  
Vol 10 (11) ◽  
pp. 2374-2381
Author(s):  
YAEL SEGEV ◽  
DANIEL LANDAU ◽  
RUTH RASCH ◽  
ALLAN FLYVBJERG ◽  
MOSHE PHILLIP
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Binding Protein ◽  
Somatic Growth ◽  
Nod Mice ◽  
Mrna Levels ◽  
Therapeutic Implications ◽  
Protein Levels ◽  
Nonobese Diabetic ◽  
Igf I

Abstract. The growth hormone (GH)/insulin-like growth factor (IGF) axis is involved in diabetic renal disease. The role of a specific GH receptor (GHR) antagonist in the development of early renal changes in nonobese diabetic (NOD) mice was investigated. Female diabetic (nonketotic) NOD mice treated with a polyethylene glycol-treated GHR antagonist (2 mg/kg, every other day) (DA group) or saline (D group) and their nonhyperglycemic age-matched littermates (control animals) were euthanized 3 wk after the onset of diabetes. Body weights at euthanasia were similar among the groups. Serum GH levels were markedly elevated, and serum IGF-I levels were significantly decreased in D and DA animals, compared with controls. The increases in kidney weights and glomerular volumes observed for the D group were absent in the DA group. Albuminuria was increased in the D group but was normalized in the DA group. Extractable renal IGF-I protein levels were increased in the D group but were partially normalized in the DA group. Renal IGF-binding protein 1 mRNA levels were increased in the D group but returned to almost normal levels in the DA animals. Kidney IGF-I and GHR mRNA levels were decreased in both the D and DA groups. Renal GH-binding protein mRNA levels remained unchanged in both diabetic groups. GHR antagonism had a blunting effect on renal/glomerular hypertrophy and albuminuria in diabetic NOD mice. These salutary effects were associated with concomitant inhibition of increased renal IGF-I protein levels and were obtained without affecting either somatic growth or circulating GH and IGF-I levels. Therefore, modulation of GH effects may have beneficial therapeutic implications in diabetic nephropathy.

scholarly journals Age-Related Alterations in Pituitary and Testicular Functions in Long-Lived Growth Hormone Receptor Gene-Disrupted Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6019-6025 ◽  
Author(s):  
Varadaraj Chandrashekar ◽  
Christina R. Dawson ◽  
Eric R. Martin ◽  
Juliana S. Rocha ◽  
Andrzej Bartke ◽  
...  
Keyword(s):  
Growth Hormone Receptor ◽  
Receptor Gene ◽  
Delayed Puberty ◽  
Plasma Testosterone ◽  
Mrna Levels ◽  
Testosterone Levels ◽  
Gh Receptor ◽  
Age Related ◽  
Igf I ◽  
Plasma Prl

The somatotropic axis, GH, and IGF-I interact with the hypothalamic-pituitary-gonadal axis in health and disease. GH-resistant GH receptor-disrupted knockout (GHRKO) male mice are fertile but exhibit delayed puberty and decreases in plasma FSH levels, testicular content of LH, and prolactin (PRL) receptors, whereas PRL levels are elevated. Because the lifespan of GHRKO mice is much greater than the lifespan of their normal siblings, it was of interest to compare age-related changes in the hypothalamic-pituitary-gonadal axis in GHRKO and normal animals. Plasma IGF-I, insulin, PRL, LH, FSH, androstenedione and testosterone levels, and acute responses to GnRH and LH were measured in young (2–4 and 5–6 months of age) and old (18–19 and 23–26 months of age) male GHRKO mice and their normal siblings. Plasma IGF-I was not detectable in GHRKO mice. Plasma PRL levels increased with age in normal mice but declined in GHRKO males, and did not differ in old GHRKO and normal animals. Plasma LH responses to acute GnRH stimulation were attenuated in GHRKO mice but increased with age only in normal mice. Plasma FSH levels were decreased in GHRKO mice regardless of age. Plasma testosterone responses to LH stimulation were attenuated in old mice regardless of genotype, whereas plasma androstenedione responses were reduced with age only in GHRKO mice. Testicular IGF-I mRNA levels were normal in young and increased in old GHRKO mice, whereas testicular concentrations and total IGF-I levels were decreased in these animals. These findings indicate that GH resistance due to targeted disruption of the GH receptor gene in mice leads to suppression of testicular IGF-I levels, and modifies the effects of aging on plasma PRL levels and responses of the pituitary and testes to GnRH and LH stimulation. Plasma testosterone levels declined during aging in normal but not in GHRKO mice, and the age-related increase in the LH responses to exogenous GnRH was absent in GHRKO mice, perhaps reflecting a delay of aging in these remarkably long-lived animals.

scholarly journals Reduced Growth Hormone Receptor Messenger Ribonucleic Acid in an Aged Man with Chronic Malnutrition and Growth Hormone Resistance

1999 ◽  
Vol 84 (7) ◽  
pp. 2320-2323 ◽  
Author(s):  
Yujin Shuto ◽  
Tadasumi Nakano ◽  
Naoko Sanno ◽  
Hideharu Domoto ◽  
Hitoshi Sugihara ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Ribonucleic Acid ◽  
Binding Protein ◽  
Sella Turcica ◽  
Biologically Active ◽  
Messenger Ribonucleic Acid ◽  
Gh Receptor ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

A severely malnourished 87-yr-old man presented with hypoglycemia. Serum GH levels were elevated, and serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3, and GH-binding protein were extremely reduced. The patient’s GH was biologically active. Administration of GH for 4 consecutive days resulted in a slight increment in serum IGF-I levels, but no elevation of serum IGF-binding protein-3. The expression of GH receptor messenger ribonucleic acid in the liver was greatly reduced. An autopsy revealed a Rathke’s cleft cyst confined to the sella turcica. Immunohistochemical studies for GH showed that there was nothing to suggest a tumor overproducing GH. In addition, TSH levels were elevated in the presence of normal thyroid hormone levels, and there was a cluster of cells showing strong immunohistochemical staining for the TSH β-subunit in the pituitary. In this patient, the decreased expression of GH receptor messenger ribonucleic acid in the liver may have been responsible for the GH resistance, which was probably caused by malnutrition.

Growth hormone-binding protein-related immunoreactivity in the serum of patients with acromegaly is regulated inversely by growth hormone concentration

1995 ◽  
Vol 132 (3) ◽  
pp. 306-312 ◽  
Author(s):  
Jürgen Kratzsch ◽  
Werner F Blum ◽  
Manfred Ventz ◽  
Thomas Selisko ◽  
Gerd Birkenmeyer ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Binding Protein ◽  
Receptor Density ◽  
Hormone Concentration ◽  
Hormone Binding ◽  
Gh Receptor ◽  
Growth Hormone Binding Protein ◽  
Igf I ◽  
Hormone Binding Protein ◽  
Igfbp 3

Kratzsch J. Blum WF, Ventz M, Selisko T, Birkenmeyer G, Keller E. Growth hormone-binding proteinrelated immunoreactivity in the serum of patients with acromegaly is regulated inversely by growth hormone concentration. Eur J Endocrinol 1994;132:306–12. ISSN 0804–4643 In this report we describe a newly developed radioimmunoassay (RIA) for the determination of the high-affinity growth hormone-binding protein (GHBP) in human blood. Using this RIA for the measurement of GHBP in serum of 29 patients with acromegaly, decreased concentrations were found compared to the normal range, depending on the activity of the disease. Growth hormonebinding protein was correlated inversely to log GH (r = −0.7, p < 0.001). A weaker relationship was shown between the GHBP activity determined in a functional assay based on charcoal separation and log GH (r = −0.51, p< 0.01). While insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) were correlated directly to log GH (r = 0.77 and r = 0.66, p < 0.001), an inverse and weaker relationship was evident between GHBP measured by RIA and IGF-I or IGFBP-3 (r = −0.61 and r = −0.57,p < 0.01). In contrast, no correlation could be detected between data of the functional GHBP assay and IGF-I or IGFBP-3, These results suggest, that: (1) in patients with acromegaly the GH receptor density in tissue reflected by the GHBP serum levels seems to be down-regulated, depending on the increased GH level; (2) low GHBP concentrations indicate an active disease in acromegaly and may be of diagnostic interest; (3) presuming that the GH receptor density is related to GH sensitivity, the variation of GH sensitivity is less important for IGF-I and IGFBP-3 production than the circulating GH concentration, at least in the situation of acromegaly; (4) because endogenous GH does not interfere in that assay, the RIA provides a valuable tool for the investigation of regulations between GH, GHBP and the GH receptor, especially in patients with acromegaly. The GHBP levels may be used as a sensitive parameter of GH oversecretion and tissue sensitivity to this hormone. Jürgen Kratzsch, Inst. Clin. Chem., University of Leipzig, Paul-List-Str. 13–15, D-04103 Leipzig, Germany

Growth hormone (GH) receptor and GH-binding protein deficiency in the growth failure of potassium-depleted rats

1995 ◽  
Vol 147 (2) ◽  
pp. 253-258 ◽  
Author(s):  
Z Hochberg ◽  
T Amit ◽  
A Flyvbjerg ◽  
I Dørup
Keyword(s):  
Growth Hormone ◽  
Growth Retardation ◽  
Binding Protein ◽  
Growth Failure ◽  
Correlation Coefficients ◽  
Young Female ◽  
Gh Receptor ◽  
Liver Membranes ◽  
Serum Gh ◽  
Gh Receptors

Abstract Potassium (K+) deficiency is associated with growth retardation in both man and experimental animals. Growth hormone (GH) administration to such animals prevents, to some extent, weight loss and selective muscle atrophy, but does not affect tail and tibia length even with supraphysiological doses. The present study was undertaken to investigate the possible effect of K+ deficiency on the hepatic GH receptor and GH-binding protein (BP). Young female Wistar rats were maintained on K+-deficient fodder and distilled water, and compared with pair-fed and ad-libitumfed control groups. After 15 days GH-BP and electrolytes were measured in sera, GH receptors were studied in liver membranes by 125I-labeled human GH binding and muscles were weighed and saved for electrolyte measurements. K+-deficient rats showed complete growth arrest compared with an intermediate weight gain of the pair-fed group. Serum K+ was very low, at 1·5 ±0·1 mmol/l, compared with the mean value of 5·3 mmol/l of control animals. Somatogenic and lactogenic receptors in liver membranes and serum GH-BP levels were significantly (P<0·05) lower in K+ deficiency, as compared with their pair-fed controls. Liver GH receptors correlated significantly (P<0·05) with serum GH-BP levels. The growth variables correlated positively with both hepatic somatogenic and lactogenic receptors and serum GH-BP levels, with correlation coefficients that were highest against serum GH-BP and lowest against liver lactogenic receptors. Serum and muscle K+ correlated significantly (P<0·05) with both liver GH receptors and serum GH-BP, with correlation coefficients that were higher against serum GH-BP. Lactogenic receptors had a lower or no correlation. It is concluded that GH receptor deficiency may be involved in the growth retardation of K+ deficiency. Journal of Endocrinology (1995) 147, 253–258

Somatostatin regulates hepatic growth hormone sensitivity by internalizing growth hormone receptors and by decreasing transcription of growth hormone receptor mRNAs

2007 ◽  
Vol 292 (5) ◽  
pp. R1956-R1962 ◽  
Author(s):  
Nicole M. Very ◽  
Mark A. Sheridan
Keyword(s):  
Growth Hormone ◽  
Steady State ◽  
Growth Hormone Receptor ◽  
Hormone Receptors ◽  
Binding Capacity ◽  
Isolated Hepatocytes ◽  
Receptor Internalization ◽  
Dependent Manner ◽  
Growth Hormone Receptors ◽  
Steady State Levels

Somatostatins (SSs), a diverse family of peptide hormones, have been shown to inhibit the release of growth hormone (GH) from the pituitary. In this study, we used rainbow trout to determine whether or not SSs affect growth in an extrapituitary manner, in particular, by decreasing GH sensitivity in liver. SS-14 significantly decreased hepatic GH binding in fish implanted (5.8 × 10−11 mol/h) for 15 days and in isolated hepatocytes. The processing of 125I-labeled trout GH (tGH) by isolated hepatocytes was investigated to determine whether or not the decrease in GH binding capacity resulted from receptor internalization. The internalization of 125I-labeled tGH was time dependent. By 6 h, 100 ng/ml SS-14 increased internalization of 125I-labeled tGH 58% over that observed in controls. Steady-state levels of mRNAs encoding the two hepatic growth hormone receptors (GHRs) of trout, GHR 1 and GHR 2, were measured to determine whether or not decreased GH binding capacity also resulted from decreased GHR synthesis. SS-14 directly inhibited steady-state levels of GHR 1 and GHR 2 mRNA in isolated hepatocytes in a concentration-dependent manner. The inhibitory effects of SS-14 on steady-state levels of GHR mRNAs resulted from reduced GHR mRNA transcription and not from altered mRNA stability. These results indicate that SSs regulate hepatic GH sensitivity by increasing GHR internalization and by altering GHR expression and suggest that SSs coordinate growth at the level of the pituitary, as well as at extrapituitary levels.

Characterization of the growth hormone receptor in human dermal fibroblasts and liver during development

2001 ◽  
Vol 281 (6) ◽  
pp. E1213-E1220 ◽  
Author(s):  
Cynthia G. Goodyer ◽  
Rilene M. O. Figueiredo ◽  
Stephanie Krackovitch ◽  
Lilia De Souza Li ◽  
Jennifer A. Manalo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Hormone Receptors ◽  
Fetal Liver ◽  
Dermal Fibroblasts ◽  
Igf Binding Proteins ◽  
Fourfold Increase ◽  
Fetal Hepatocytes ◽  
Age Related ◽  
Fetal Hepatocyte

Human tissues express growth hormone receptors (hGHR) by the 3rd mo of gestation. We assessed developmental changes in hGHR function in fibroblasts and liver, testing binding and hormonal response. Fetal cells showed low but reproducible hGH binding. No age-related changes occurred in fibroblasts (9 wk–34 yr). In contrast, there was a fourfold increase in hGH binding in postnatal liver, with a sixfold increase in hGHR mRNA. Both full-length and truncated hGHR mRNAs were detected in all livers. Cross-linking revealed a larger hGH/receptor complex in fetal liver. Fetal hepatocytes produced 10 times more insulin-like growth factor (IGF)-II than IGF-I, and responded to hGH (150 ng/ml) with a significant increase in IGF-II. Fetal hepatocytes secreted three IGF-binding proteins (IGFBPs), including IGFBP1, but not IGFBP3. hGH did not alter fetal hepatocyte IGFBPs but stimulated glucose uptake. Exposure of fibroblasts to hGH decreased hGH binding only in >1-yr postnatal fibroblasts, whereas treatment with dexamethasone (100–400 nM) increased binding only in postnatal cells. Thus, although fetal hepatocytes and fibroblasts possess functional hGHR, these receptors (and/or their signaling pathways) are immature or have adapted to the in utero environment.

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