Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis.
Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis.
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DOI：
10.1172/jci19933
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发表时间：
2004-08
期刊：
影响因子：
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通讯作者：
R. Murray;Kiwon Kim;S. Ren;M. Chelly;Y. Umehara;S. Melmed
中科院分区：
文献类型：
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作者：
R. Murray;Kiwon Kim;S. Ren;M. Chelly;Y. Umehara;S. Melmed
生长抑素(SRIF)类似物为肢端肥大症提供了安全有效的治疗方法。然而，在部分患者中，SRIF类似物可能导致不协调的生长激素(GH)和IGF-I抑制，这表明一个比单独抑制GH释放更复杂的机制。为了阐明SRIF是否外周作用于GH-IGF-I轴，我们发现大鼠肝细胞表达生长抑素受体亚型-2和-3，并且给予奥曲肽以剂量依赖的方式抑制IGF-I的mRNA和蛋白水平。SRIF在不加GH的情况下抑制作用不明显，GH存在时，SRIF对IGF-I的诱导作用是特异的，不抑制GH诱导的c-myc或细胞外信号调节激酶(ERK)的磷酸化。用百日咳毒素处理GH和SRIF或GH和奥曲肽共同孵育的肝细胞，可消除对GH诱导的IGF-I的抑制作用，这证实了抑制G蛋白的需要。SRIF和GH处理提高了蛋白酪氨酸磷酸酶(PTP)的活性，抑制了信号转导和转录激活因子-5b(STAT5b)的磷酸化和核定位。奥曲肽还能抑制GH刺激的大鼠肝脏IGF-I蛋白含量。结果表明，SRIF具有中枢和外周调节GH-IGF-I轴的作用，为SRIF类似物在治疗GH-分泌性垂体腺瘤中的作用提供了机制解释。
Somatostatin (SRIF) analogs provide safe and effective therapy for acromegaly. In a proportion of patients, however, SRIF analogs may lead to discordant growth hormone (GH) and IGF-I suppression, which suggests a more complex mechanism than attributable to inhibition of GH release alone. To elucidate whether SRIF acts peripherally on the GH-IGF-I axis, we showed that rat hepatocytes express somatostatin receptor subtypes-2 and -3 and that IGF-I mRNA and protein levels were suppressed in a dose-dependent manner by administration of octreotide. The inhibitory effect of SRIF was not apparent without added GH and in the presence of GH was specific for IGF-I induction and did not inhibit GH-induced c-myc or extracellular signal regulated kinase (ERK) phosphorylation. Pertussis toxin treatment of hepatocytes incubated with GH and SRIF, or with GH and octreotide, abrogated the inhibitory effect on GH-induced IGF-I, which confirms the requirement for the inhibitory G-protein. Treatment with SRIF and GH increased protein tyrosine phosphatase (PTP) activity and inhibited signal transducer and activator of transcription-5b (STAT5b) phosphorylation and nuclear localization. Octreotide also inhibited GH-stimulated IGF-I protein content of ex vivo-perfused rat livers. The results demonstrate that SRIF acts both centrally and peripherally to control the GH-IGF-I axis, providing a mechanistic explanation for SRIF analog action in treating patients with GH-secreting pituitary adenomas.