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Cirrhotic Liver Expresses Low Levels of the Full-Length and Truncated Growth Hormone Receptors¹

Department of Medicine, Clinical Sciences Center, Sheffield University, Sheffield, United Kingdom S5 7AU; the Department of Medicine (R.I.G.H., J.P.M.), Institute of Liver Studies (B.P.), King’s College Hospital, London, United Kingdom SE5 9PJ; and INSERM U-344, Endocrinologie Moleculaire, Faculte de Medecine Necker (M.-C.P.-V.), 75730 Paris, France

Address all correspondence and requests for reprints to: Dr. R. J. M. Ross, Department of Medicine, Clinical Sciences, Northern General Hospital, Sheffield, United Kingdom S5 7AU. E-mail: r.j.ross{at}sheffield.ac.uk

In cirrhosis, as in other conditions of protein catabolism, there is a state of acquired GH resistance, as defined by high circulating GH levels with low insulin-like growth factor I levels. However, patients with end-stage liver failure respond to supraphysiological doses of GH with an increase in circulating insulin-like growth factor I levels. The present study represents a detailed analysis of GH receptor (GHR) expression in cirrhotic liver from 17 patients with end-stage liver disease. Specific binding of labeled GH was identified in all cirrhotic livers studied. The binding affinity for the GHR was similar in cirrhotic and normal livers, but the number of binding sites per mg protein of liver membrane was variable in both normal and cirrhotic liver, although it were generally lower in cirrhotic liver. GHR expression was identified in cirrhotic liver by Northern blotting, RT-PCR, and ribonuclease protection assay. On Northern blotting, a single transcript of 4.8 kb was identified in normal and cirrhotic tissues. RT-PCR identified expression of both full-length GHR and a truncated form of the GHR; this was confirmed by ribonuclease protection assay. In situ hybridization and immunohistochemistry confirmed the expression of GHR in regenerating hepatocytes and isolated cells in fibrous tissue. In conclusion, 1) the low level of GHR in cirrhotic liver may contribute to the acquired GH resistance found in cirrhotic patients; 2) the reduced expression of both full-length and truncated GHR is compatible with the low level of GH-binding protein found in cirrhosis, as this truncated receptor has previously been reported to generate large amounts of GH-binding protein; and 3) the demonstration of GH binding to cirrhotic liver explains why these patients with GH resistance may still respond to supraphysiological doses of GH.

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