This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leung, K.-C. Articles by Ho, K. K. Y. Search for Related Content PubMed PubMed Citation Articles by Leung, K.-C. Articles by Ho, K. K. Y.

Insulin Regulation of Human Hepatic Growth Hormone Receptors: Divergent Effects on Biosynthesis and Surface Translocation¹

Pituitary Research Unit, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales 2010; and Department of Physiology and Pharmacology, Center for Molecular and Cellular Biology, University of Queensland (M.J.W.), St. Lucia, Queensland 4072, Australia

Address all correspondence and requests for reprints to: Dr. Kin-Chuen Leung, Pituitary Research Unit, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia. E-mail: k.leung{at}garvan.unsw.edu.au

Insulin modulates the biological actions of GH, but little is known about its effect on human hepatic GH receptors (GHRs). Using the human hepatoma cell line HuH7 as a model, we investigated insulin regulation of total, intracellular, and cell surface GHRs and receptor biosynthesis and turnover. Insulin up-regulated total and intracellular GHRs in a concentration-dependent manner. It increased surface GHRs in a biphasic manner, with a peak response at 10 nmol/L, and modulated GH-induced Janus kinase-2 phosphorylation in parallel with expression of surface GHRs. The abundance of GHR messenger ribonucleic acid and protein, as assessed by RT-PCR and Western analysis, respectively, markedly increased with insulin treatment. To examine whether insulin regulates GHRs at the posttranslational level, its effects on receptor surface translocation and internalization were investigated. Insulin suppressed surface translocation in a concentration-dependent manner, whereas internalization was unaffected. Moreover, insulin actions on total GHRs and surface translocation were inhibited by PD98059 and wortmannin, respectively. In conclusion, insulin regulates hepatic GHR biosynthesis and surface translocation in a reciprocal manner, with surface receptor availability the net result of the divergent effects. The divergent actions of insulin appear to be mediated by the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, respectively.

This article has been cited by other articles:

				J. Frystyk, R. A. Ritzel, J. Maubach, M. Busing, R. Luck, J. Klempnauer, W. Schmiegel, and M. A. Nauck Comparison of Pancreas-Transplanted Type 1 Diabetic Patients with Portal-Venous Versus Systemic-Venous Graft Drainage: Impact on Glucose Regulatory Hormones and the Growth Hormone/Insulin-Like Growth Factor-I Axis J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1758 - 1766. [Abstract] [Full Text] [PDF]

				G. Iniguez, K. Ong, R. Bazaes, A. Avila, T. Salazar, D. Dunger, and V. Mericq Longitudinal Changes in Insulin-Like Growth Factor-I, Insulin Sensitivity, and Secretion from Birth to Age Three Years in Small-for-Gestational-Age Children J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4645 - 4649. [Abstract] [Full Text] [PDF]

				Y. Wei, Z. Rhani, and C. G. Goodyer Characterization of Growth Hormone Receptor Messenger Ribonucleic Acid Variants in Human Adipocytes J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1901 - 1908. [Abstract] [Full Text] [PDF]

				P. Rittler, B. Schiefer, H. Demmelmair, B. Koletzko, M. Vogeser, D. H. Alpers, K.-W. Jauch, and W. H. Hartl The Effect of Hyperglycemic Hyperinsulinemia on Small-Intestinal Mucosal Protein Synthesis in Patients After Surgical Stress JPEN J Parenter Enteral Nutr, March 1, 2006; 30(2): 97 - 107. [Abstract] [Full Text] [PDF]

				A. Flores-Morales, C. J. Greenhalgh, G. Norstedt, and E. Rico-Bautista Negative Regulation of Growth Hormone Receptor Signaling Mol. Endocrinol., February 1, 2006; 20(2): 241 - 253. [Abstract] [Full Text] [PDF]

				U. Espelund, J. M. Bruun, B. Richelsen, A. Flyvbjerg, and J. Frystyk Pro- and mature IGF-II during diet-induced weight loss in obese subjects Eur. J. Endocrinol., December 1, 2005; 153(6): 861 - 869. [Abstract] [Full Text] [PDF]

				H. K. Gleeson, C. A. Lissett, and S. M. Shalet Insulin-Like Growth Factor-I Response to a Single Bolus of Growth Hormone Is Increased in Obesity J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1061 - 1067. [Abstract] [Full Text] [PDF]

				J.-W. Chen, K. Hojlund, H. Beck-Nielsen, J. Sandahl Christiansen, H. Orskov, and J. Frystyk Free Rather than Total Circulating Insulin-Like Growth Factor-I Determines the Feedback on Growth Hormone Release in Normal Subjects J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 366 - 371. [Abstract] [Full Text] [PDF]

				R. Coutant, F. B. de Casson, S. Rouleau, O. Douay, E. Mathieu, F. Gatelais, N. Bouhours-Nouet, C. Voinot, M. Audran, and J. M. Limal Divergent Effect of Endogenous and Exogenous Sex Steroids on the Insulin-Like Growth Factor I Response to Growth Hormone in Short Normal Adolescents J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6185 - 6192. [Abstract] [Full Text] [PDF]

				C. A. Hedman, J. Frystyk, T. Lindstrom, J.-W. Chen, A. Flyvbjerg, H. Orskov, and H. J Arnqvist Residual {beta}-Cell Function More than Glycemic Control Determines Abnormalities of the Insulin-Like Growth Factor System in Type 1 Diabetes J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6305 - 6309. [Abstract] [Full Text] [PDF]

				P. Kotokorpi, C. Gardmo, C. S. Nystrom, and A. Mode Activation of the Glucocorticoid Receptor or Liver X Receptors Interferes with Growth Hormone-Induced akr1b7 Gene Expression in Rat Hepatocytes Endocrinology, December 1, 2004; 145(12): 5704 - 5713. [Abstract] [Full Text] [PDF]

				M. M. Buijs, J. A. Romijn, J. Burggraaf, M. L. de Kam, M. Frolich, M. T. Ackermans, H. P. Sauerwein, A. F. Cohen, A. E. Meinders, and H. Pijl Glucose homeostasis in abdominal obesity: hepatic hyperresponsiveness to growth hormone action Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E63 - E68. [Abstract] [Full Text] [PDF]

				R. P. Rhoads, J. W. Kim, B. J. Leury, L. H. Baumgard, N. Segoale, S. J. Frank, D. E. Bauman, and Y. R. Boisclair Insulin Increases the Abundance of the Growth Hormone Receptor in Liver and Adipose Tissue of Periparturient Dairy Cows J. Nutr., May 1, 2004; 134(5): 1020 - 1027. [Abstract] [Full Text] [PDF]

				T. K. Hansen, C. H. Gravholt, H. Orskov, M. H. Rasmussen, J. S. Christiansen, and J. O. L. Jorgensen Dose Dependency of the Pharmacokinetics and Acute Lipolytic Actions of Growth Hormone J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4691 - 4698. [Abstract] [Full Text] [PDF]

				T. K. Hansen, J. O. L. Jorgensen, and J. S. Christiansen Body Composition and Circulating Levels of Insulin, Insulin-Like Growth Factor-Binding Protein-1 and Growth Hormone (GH)-Binding Protein Affect the Pharmacokinetics of GH in Adults Independently of Age J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2185 - 2193. [Abstract] [Full Text] [PDF]

				R. Coutant, F. Boux de Casson, S. Rouleau, O. Douay, E. Mathieu, M. Audran, and J. M. Limal Body Composition, Fasting Leptin, and Sex Steroid Administration Determine GH Sensitivity in Peripubertal Short Children J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5805 - 5812. [Abstract] [Full Text] [PDF]