Metformin inhibits growth hormone-mediated hepatic PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner.
Metformin inhibits growth hormone-mediated hepatic PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner.
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二甲双胍通过诱导孤儿核受体小型异二聚体伴侣抑制生长激素介导的肝PDK4基因表达。
作者：
Kim YD;Kim YH;Tadi S;Yu JH;Yim YH;Jeoung NH;Shong M;Hennighausen L;Harris RA;Lee IK;Lee CH;Choi HS
生长激素（GH）是一种反调节激素，在预防禁食期间发生低血糖方面发挥着重要作用。由于丙酮酸脱氢酶激酶 4 (PDK4) 对丙酮酸脱氢酶复合物 (PDC) 的抑制保留了糖异生的底物，因此我们测试了 GH 是否通过对二甲双胍抑制敏感的信号通路增加肝脏中 PDK4 的表达。 GH 和二甲双胍的作用是在野生型、小异二聚体伴侣 (SHP)、PDK4 和信号转导子和转录激活子 5 (STAT5) 缺失小鼠的肝脏中测定的。体内施用 GH 通过依赖于 STAT5 磷酸化的途径增加 PDK4 表达。二甲双胍通过依赖于 AMP 激活蛋白激酶 (AMPK) 和 SHP 诱导的途径抑制 GH 对 PDK4 表达的诱导。在 STAT5 缺失小鼠中，GH 引起的 PDK4 表达增加和 PDC 磷酸化减少。二甲双胍在野生型小鼠中减少了 GH 介导的 PDK4 表达和代谢物的诱导，但在 SHP 缺失小鼠中则没有这种作用。在原代肝细胞中，显性失活突变体 AMPK 和 SHP 敲低阻止了二甲双胍对 GH 刺激的 PDK4 表达的抑制作用。 SHP 直接抑制 PDK4 基因启动子上的 STAT5 结合。二甲双胍通过 AMPK-SHP 依赖性途径抑制 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介导途径诱导的肝脏代谢紊乱提供一种新的治疗方法。
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.
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影响因子：
4.1
作者：
Sanders, Matthew J.;Grondin, Pascal O.;Carling, David
通讯作者：
Carling, David
DOI：
10.1016/j.advenzreg.2003.11.020
发表时间：
2004-01-01
期刊：
ADVANCES IN ENZYME REGULATION, VOL 44
影响因子：
--
作者：
Kwon, HS;Harris, RA
通讯作者：
Harris, RA
影响因子：
4.8
作者：
Chia, DJ;Ono, M;Rotwein, P
通讯作者：
Rotwein, P
影响因子：
4
作者：
MACLEOD, JN;PAMPORI, NA;SHAPIRO, BH
通讯作者：
SHAPIRO, BH
DOI：
10.1152/ajpendo.1996.270.1.e107
发表时间：
1996-01-01
影响因子：
5.1
作者：
Pincus, SM;Gevers, EF;Veldhuis, JD
通讯作者：
Veldhuis, JD