National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Diabetes. 2012 Oct;61(10):2484-94. doi: 10.2337/db11-1665. Epub 2012 Jun 14.
Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP-dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
生长激素（GH）是一种对抗性激素，在禁食期间防止低血糖发挥重要作用。由于丙酮酸脱氢酶复合物（PDC）被丙酮酸脱氢酶激酶 4（PDK4）抑制可使糖异生的底物得到保存，我们检测了 GH 是否通过对二甲双胍敏感的信号通路增加肝脏中的 PDK4 表达。在野生型、小异二聚体伴侣（SHP）-、PDK4-和信号转导和转录激活因子 5（STAT5）-基因敲除小鼠的肝脏中测定 GH 和二甲双胍的作用。体内给予 GH 可通过依赖 STAT5 磷酸化的途径增加 PDK4 表达。二甲双胍通过依赖 AMP 激活的蛋白激酶（AMPK）和 SHP 诱导的途径抑制 GH 诱导的 PDK4 表达。STAT5 基因敲除小鼠中 GH 增加 PDK4 表达和 PDC 磷酸化的作用减弱。二甲双胍降低了野生型小鼠中 GH 介导的 PDK4 表达和代谢物的增加，但在 SHP 基因敲除小鼠中没有。在原代肝细胞中，显性失活突变型-AMPK 和 SHP 敲低可阻止二甲双胍对 GH 刺激的 PDK4 表达的抑制作用。SHP 直接抑制 STAT5 与 PDK4 基因启动子的结合。二甲双胍通过 AMPK-SHP 依赖途径抑制 GH 诱导的 PDK4 表达和代谢物。二甲双胍-AMPK-SHP 网络可能为治疗 GH 介导的途径引起的肝代谢紊乱提供一种新的治疗方法。
