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Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein
R I Holt1, P A Crossey, J S Jones
1Department of Medicine, King's College School of Medicine and Dentistry, London, UK.
Insights
Children with end-stage liver disease show altered serum insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBPs). Hepatic gene expression changes in growth hormone receptor and IGF-I may explain reduced IGF-I, but not IGFBP alterations.
Area of Science:
- Pediatric Gastroenterology
- Hepatology
- Endocrinology
Background:
- End-stage liver disease (ESLD) in children is associated with significant changes in body composition and serum levels of insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBPs).
- The underlying molecular mechanisms, particularly hepatic gene expression, driving these alterations in pediatric ESLD remain incompletely understood.
Purpose of the Study:
- To investigate the relationship between serum IGF-I and IGFBP levels and their corresponding hepatic messenger RNA (mRNA) expression in children with end-stage extrahepatic biliary atresia.
- To determine if changes in hepatic gene expression correlate with liver dysfunction or body composition in this pediatric population.
Main Methods:
- Serum samples and liver tissue (from donors) were analyzed from 11 children with biliary atresia awaiting transplantation and 11 controls.
- Serum IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 levels were quantified using radioimmunoassay and immunoradiometric assay.
- Hepatic mRNA expression of growth hormone receptor, IGF-I, and IGFBP-1 to -4 was assessed using quantitative reverse transcription-polymerase chain reaction, ribonuclease protection assay, and Northern analysis.
Main Results:
- Children with biliary atresia exhibited significantly reduced hepatic mRNA expression of growth hormone receptor (1.7-fold) and IGF-I (9.6-fold) compared to controls.
- Despite altered serum IGFBP-1 and IGFBP-3 levels, their hepatic mRNA expression remained unchanged.
- Serum levels and hepatic mRNA expression of IGFBP-2 were significantly increased (1.6-fold and 2-fold, respectively) in children with biliary atresia.
Conclusions:
- Reduced hepatic growth hormone receptor and IGF-I mRNA expression likely contribute to the decreased serum IGF-I observed in pediatric liver disease.
- Significant alterations in circulating IGFBP levels, particularly IGFBP-2, are not fully explained by changes in hepatic gene expression, suggesting a crucial role for posttranslational modifications.
Abstract:
Major changes in serum levels of insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBPs) occur in children with end-stage liver disease in association with changes in body composition. We hypothesized that these changes would be associated with changes in hepatic messenger RNA (mRNA) expression. Eleven children with end-stage extrahepatic biliary atresia and 11 controls (liver donors) were studied. Serum samples were obtained from the children with biliary atresia immediately before orthotopic liver transplantation. Serum IGF-I, IGFBP-1, and IGFBP-2 levels were measured by radioimmunoassay, and IGFBP-3 by immunoradiometric assay. In both groups, growth hormone receptor mRNA expression was examined by quantitative reverse transcription-polymerase chain reaction, IGF-I mRNA expression by ribonuclease protection assay, and IGFBP-1 to -4 mRNA expression by Northern analysis. Growth hormone receptor and IGF-I mRNA levels were reduced 1.7-fold (P = .003) and 9.6-fold (P = .0001) in biliary atresia compared with levels in controls. Despite increased serum IGFBP-1 levels and reduced IGFBP-3 levels in biliary atresia, there was no change in either IGFBP-1 or IGFBP-3 mRNA expression. In contrast, serum levels and mRNA expression of IGFBP-2 were increased 1.6-fold (P = .003) and twofold (P = .0001), respectively, compared with controls. Gene expression did not correlate with liver dysfunction or body composition. Changes in growth hormone receptor and IGF-I mRNA expression may account for the reduction in serum IGF-I found in pediatric liver disease. In contrast, the marked alteration in circulating IGFBP levels was not accompanied by changes in hepatic IGFBP gene expression, suggesting that posttranslational mechanisms may be important.