ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2004) 8 P22

Somatostatin Abrogates GH-Induced Hepatocyte IGF-I Transcription by Inhibiting STAT5b Phosphorylation amp Nuclear Translocation

RD Murray, K Kim, Y Umehara & S Melmed

Cedars Sinai Research Institute, UCLA School of Medicine, Los Angeles, California, 90048.

Use of somatostatin (SRIF) analogs in acromegaly indicates greater lowering of IGF-I than predicted from GH reduction. Studies using hypophysectomized rats suggest a direct SRIF action on GH-induced IGF-I, however, interpretation is complicated by effects of SRIF on other hormonal axes. In isolated rat hepatocytes we showed SRIF and octreotide to have a direct inhibitory effect, via hepatic SSTRs, on GH-induced IGF-I production. GH (500 ng/ml) caused ~4 fold induction of IGF-I mRNA at 24 hrs (p = 0.02). SRIF and octreotide (100nM) inhibited GH-induced IGF-I transcription by ~50%. GH increased pERK of cultured rat hepatocytes in a time dependent manner with maximal levels at 5 to 10 minutes. Co-incubation with GH and SRIF did not alter the temporal or quantitative effect of GH on ERK phosphorylation. Hepatocyte cultures incubated with GH in the presence or absence of SRIF or octreotide for 30 minutes did not abrogate GH increased c-myc levels. Hepatocytes incubated with cycloheximide 10 mg/ml before treatment with SRIF and GH did not abrogate SRIF inhibition of GH-induced IGF-I. GH-induced SOCS2 and SOCS3 were not further enhanced by co-incubation with SRIF. No increase in PTP activity was detected with either ligand alone, however, the combination of GH and SRIF led to a synergistic increase in PTP activity to 36% above baseline (p < 0.05). GH increased phosphorylation of STAT5b, whereas in the presence of SRIF, GH failed to phosphorylate STAT5b. GH induced nuclear STAT5 levels were attenuated by SRIF.

In the hepatocyte the inhibitory effect of SRIF on GH stimulated pathways is specific for IGF-I and does not abrogate pathways involved in GH regulation of cellular growth and differentiation. SRIF inhibition of GH-induced IGF-I does not require translation of a protein intermediate, but likely acts with GH to synergistically induce PTP resulting in subsequent STAT5b dephosphorylation, and a reduction in nuclear STAT5b translocation.

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