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

Abstract

interrelationship between and the regulation of hepatic growth hormone receptors and circulating GH binding protein in the pig. Acta Endocrinol 1992;126:155-61. 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 \ m=+-\ 1.2 (mean\m=+-\1 x sem) (controls) to 17.8 \m=+-\2.0% in infants, and from 35.2 \m=+-\2.6(controls) to 41.8 \ m=+-\ 3.4% in pubertal animals.[125I]bGH binding to hepatic membranes was also increased by rpGH treatment (p<0.05), from 7.0\m=+-\1.6(controls) to 15.4\m=+-\3.6% in infants and from 53.7\m=+-\7.1(controls) to 65.1\m=+-\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. PD Gluckman, Considerable evidence exists that the hepatic growth hormone receptor is under active regulation. GH itself has a major influence on GH receptor density and chronic GH therapy has been shown to increase the number of GH receptors in both hepatic (1-3) and adipose (4) tissue. Indirect evidence suggests similar regulation by GH in growth plate (5-7).Hepatic GH receptors are also under ontogenic regula¬ tion. Prenatal somatic growth is thought not to be significantly influenced by GH, with the GH receptor in the liver appearing either very late prenatally or early postnatally (8). In the developing pig we have demon¬ strated a 14-fold increase in the capacity of the hepatic GH receptor between 2 and 165 days of age, with significant increases in receptor number not occurring until after 3 5 days of age ( 9 ). However, the earliest age at which animals or man will demonstrate a biological response to GH administration is not clearly defined.A specific GH binding protein (GH BP) has been recently demonstrated in the serum of a number of species (10-12). This GH BP appears to be largel...

Growth hormone-binding proteins: state of the art

“…Both are developmentaDy up-regulated dur¬ ing childhood, but the low-affinity GHBP peaks before age 10, whereas the high-affinity GHBP continues to rise until the late teens , Mérimée et al 1990, 1992, Tar et al 1990. A similar developmental trend occurs in the rat (Mulumba et al 1991, Carmignac et al 1992) and in the pig (Ambler et al 1992). In adult humans, there is little change in serum levels of either GHBP over time , Baumann et al 1989a, Mercado et al 1993a.…”

“…Thus, the regulation of GHBP by GH in man is far from clear, and additional studies are required to address this issue more fully. In rodents and pigs, GHBP is clearly dependent on and up-regulated by GH (Ambler et al 1992, Carmignac et al 1992, although that, too, may depend on the mode of GH administration (Maiter et al 1992). Insulin is another possible regulatory factor for GHBP, as indicated by low GHBP levels in insulin-dependent diabetes and their reversal toward normal with insulin treatment (Mercado et al 1992, Massa et al 1993.…”

Physiology and pathophysiology of growth hormone-binding protein: Methodological and clinical aspects

“…Gene expression of GHR in the liver increases after GH treatment [303][304][305], whereas in muscle, region-specific changes are described, with either higher, lower or unchanged expression of GHR. Levels of GHBP are reported increased or unaltered after GH treatment [303,305]. During food restriction in pigs GHBP levels decrease, whereas tissue-specific alterations are seen in GHR gene expression and GH binding to liver and muscle cells.…”

Effects of Intermittent Growth Hormone or Insulin-Like Growth Factor 1 Administration in the Neonatal Dwarf Rat

“…In normal young infant pigs (age 18-20 days), administration of bGH for 12 days was asso ciated with increases in serum IGF-1, hepatic GH recep tor concentrations and serum GH-binding protein [7]. Also, GH receptors have now been identified in a variety of fetal tissues in the sheep and human [21,22], and GH has been shown to stimulate DNA synthesis in human fetal hepatocytes in vitro [23].…”

“…Recent data from animal and human studies how ever suggest that GH and IGF-1 may be important growth factors in early life. Infant pigs have been shown to have a somatogenic response to GH administration [7], and a GH dependence of growth has been recently demon strated in hypophysectomized neonatal rats [8,9]. In clin ical studies there is now evidence that infants diagnosed with congenital GH deficiency are short at birth and have progressive growth failure during the first 6 months of life we examined the effects of GH or IGF-1 administration on growth, serum IGF-1, body composition and hepatic GH receptor-specific binding in the neonatal GH-deficient rat.…”