Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models
Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models
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DOI：
10.1007/s00125-012-2494-4
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发表时间：
2012-05-01
期刊：
影响因子：
8.2
通讯作者：
Choi, H. S.
中科院分区：
文献类型：
--
作者：
Kim, Y. D.;Kim, Y. H.;Choi, H. S.
目的/假设IL-6是一种与肝脏疾病发病机制相关的促炎细胞因子。二甲双胍是一种用于治疗2型糖尿病的抗糖尿病药物，孤儿核受体小异源二聚体伴侣（SHP，也称为NR 0 B2）是一种转录辅阻遏物，在维持代谢稳态中起重要作用。在这里，我们证明二甲双胍介导的AMP活化蛋白激酶（AMPK）的活化增加了SHP蛋白的产生并调节了IL-6诱导的肝脏胰岛素抵抗。方法我们研究了二甲双胍介导的SHP产生通过调节IL-6依赖性途径改善胰岛素抵抗（涉及信号转导和转录激活因子3 [STAT 3]和细胞因子信号转导抑制因子3 [SOCS 3]）。诱导的STAT 3反式激活和SOCS 3产生被二甲双胍、腺病毒组成型活性AMPK（Ad-CA-AMPK）和腺病毒SHP（Ad-SHP）显著抑制，但在Shp敲低或腺病毒显性失活形式AMPK（Ad-DNAMPK）中不受抑制。染色质免疫沉淀（ChIP），免疫共沉淀（Co-IP）和蛋白定位研究表明，SHP抑制DNA结合的STAT 3的Socs 3基因启动子通过相互作用和共定位在细胞核内。在野生型小鼠中观察到急性IL-6治疗引起的炎症基因上调和肝脏胰岛素信号转导下调，但在Shp缺失小鼠中未观察到。最后，慢性IL-6暴露引起肝脏胰岛素抵抗，导致胰岛素耐受性受损和升高的胰岛素生成，这些现象在Shp null mice. Conclusion/interpretation中加重，我们的研究结果表明，SHP上调二甲双胍可以通过调节IL-6依赖性途径来预防肝脏疾病，并且这种途径可以帮助改善精氨酸介导的代谢功能障碍的发病机制。
Aims/hypothesis IL-6 is a proinflammatory cytokine associated with the pathogenesis of hepatic diseases. Metformin is an anti-diabetic drug used for the treatment of type 2 diabetes, and orphan nuclear receptor small heterodimer partner (SHP, also known as NR0B2), a transcriptional co-repressor, plays an important role in maintaining metabolic homeostasis. Here, we demonstrate that metformin-mediated activation of AMP-activated protein kinase (AMPK) increases SHP protein production and regulates IL-6-induced hepatic insulin resistance.Methods We investigated metformin-mediated SHP production improved insulin resistance through the regulation of an IL-6-dependent pathway (involving signal transducer and activator of transcription 3 [STAT3] and suppressor of cytokine signalling 3 [SOCS3]) in both Shp knockdown and Shp null mice.Results IL-6-induced STAT3 transactivation and SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK (Ad-CA-AMPK), and adenoviral SHP (Ad-SHP), but not in Shp knockdown, or with the adenoviral dominant negative form of AMPK (Ad-DNAMPK). Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and protein localisation studies showed that SHP inhibits DNA binding of STAT3 on the Socs3 gene promoter via interaction and colocalisation within the nucleus. Upregulation of inflammatory genes and downregulation of hepatic insulin signalling by acute IL-6 treatment were observed in wild-type mice but not in Shp null mice. Finally, chronic IL-6 exposure caused hepatic insulin resistance, leading to impaired insulin tolerance and elevated gluconeogenesis, and these phenomena were aggravated in Shp null mice.Conclusions/interpretation Our results demonstrate that SHP upregulation by metformin may prevent hepatic disorders by regulating the IL-6-dependent pathway, and that this pathway can help to ameliorate the pathogenesis of cytokine-mediated metabolic dysfunction.