CIRRHOTIC LIVER EXPRESSES LOW-LEVELS OF THE FULL-LENGTH AND TRUNCATEDGROWTH-HORMONE RECEPTORS

In cirrhosis, as in other conditions of protein catabolism, there is a state of acquired GH resistance, as defined by high circulating GH le vels with low insulin-like growth factor I levels. However, patients w ith end-stage liver failure respond to supraphysiological doses of GH with an increase in circulating insulin-like growth factor I levels. T he present study represents a detailed analysis of GH receptor (GHR) e xpression in cirrhotic liver from 17 patients with end-stage liver dis ease. Specific binding of labeled GH was identified in all cirrhotic l ivers studied. The binding affinity for the GHR was similar in cirrhot ic and normal livers, but the number of binding sites per mg protein o f liver membrane was variable in both normal and cirrhotic liver, alth ough it were generally lower in cirrhotic liver. GHR expression was id entified in cirrhotic liver by Northern blotting, RT-PCR, and ribonucl ease 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; t his was confirmed by ribonuclease protection assay. In situ hybridizat ion and immunohistochemistry confirmed the expression of GHR in regene rating hepatocytes and isolated cells in fibrous tissue. In conclusion , 1) the low level of GHR in cirrhotic liver may contribute to the acq uired GH resistance found in cirrhotic patients; 2) the reduced expres sion of both full-length and truncated GHR is compatible with the low level of GH-binding protein found in cirrhosis, as this truncated rece ptor has previously been reported to generate large amounts of GH-bind ing protein; and 3) the demonstration of GH binding to cirrhotic liver explains why these patients with GH resistance may still respond to s upraphysiological doses of GH.