Held Matthew A, Cosme-Blanco Wilfredo, Difedele Lisa M, Bonkowski Erin L, Menon Ram K, Denson Lee A
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G986-93. doi: 10.1152/ajpgi.00287.2004. Epub 2004 Dec 16.
Children with cholestatic liver diseases, in particular biliary atresia, may develop an acquired growth hormone (GH) resistance. This is characterized by normal GH secretion, reduced liver GH receptor (GHR) abundance, and reduced circulating insulin-like growth factor I (IGF-I). Consequences include linear growth failure, reduced muscle mass, and increased perioperative morbidity and mortality. However, the molecular basis for altered GH signaling in liver and skeletal muscle in cholestatic liver disease is not known. We hypothesized that reduced IGF-I expression in obstructive cholestasis would be associated with downregulation of the GHR and impaired phosphorylation of signal transducers and activators of transcription (STAT5). Body composition was determined in C57BL/6J male mice after bile duct ligation (BDL) relative to pair-fed (PF) and ad libitum-fed controls. GHR, STAT5, Sp3, and IGF-I expression and/or DNA binding were assessed using immunoblots, electrophoretic mobility shift assays, and/or real time RT-PCR. Fat-free mass was reduced in PF mice relative to ad libitum-fed controls. BDL led to a further reduction in fat mass and fat-free mass relative to PF controls. TNF-alpha was increased in liver and skeletal muscle of BDL mice. This was associated with reduced GH-dependent STAT5 activation and IGF-I RNA expression. GHR expression was reduced in BDL mice; in liver, this was associated with reduced Sp3 binding to a GHR gene promoter cis element. Wasting in murine obstructive cholestasis is due to combined effects of reduced caloric intake and biliary obstruction. GH resistance due to downregulation of GHR expression may be attributed primarily to the obstructive cholestasis; therapies that specifically increase GHR expression may restore GH signaling in this setting.
患有胆汁淤积性肝病（尤其是胆道闭锁）的儿童可能会出现获得性生长激素（GH）抵抗。其特征是GH分泌正常、肝脏GH受体（GHR）丰度降低以及循环胰岛素样生长因子I（IGF-I）减少。后果包括线性生长障碍、肌肉量减少以及围手术期发病率和死亡率增加。然而，胆汁淤积性肝病中肝脏和骨骼肌中GH信号改变的分子基础尚不清楚。我们推测，梗阻性胆汁淤积中IGF-I表达降低会与GHR下调以及信号转导和转录激活因子（STAT5）磷酸化受损有关。相对于配对喂养（PF）和自由进食对照组，在胆管结扎（BDL）后的C57BL/6J雄性小鼠中测定身体组成。使用免疫印迹、电泳迁移率变动分析和/或实时RT-PCR评估GHR、STAT5、Sp3和IGF-I的表达和/或DNA结合情况。相对于自由进食对照组，PF小鼠的去脂体重降低。与PF对照组相比，BDL导致脂肪量和去脂体重进一步降低。BDL小鼠的肝脏和骨骼肌中肿瘤坏死因子-α增加。这与GH依赖性STAT5激活和IGF-I RNA表达降低有关。BDL小鼠的GHR表达降低；在肝脏中，这与Sp3与GHR基因启动子顺式元件的结合减少有关。小鼠梗阻性胆汁淤积中的消瘦是由于热量摄入减少和胆道梗阻共同作用的结果。由于GHR表达下调导致的GH抵抗可能主要归因于梗阻性胆汁淤积；在这种情况下，特异性增加GHR表达的疗法可能会恢复GH信号。
