Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart.
Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart.
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高血糖和高脂血症会削弱糖尿病心脏中的胰岛素-Inpp5f 负反馈回路
DOI：
10.1038/srep22068
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发表时间：
2016-02-24
影响因子：
4.6
通讯作者：
Yuan L
中科院分区：
文献类型：
--
作者：
Bai D;Zhang Y;Shen M;Sun Y;Xia Q;Zhang Y;Liu X;Wang H;Yuan L
糖尿病患者的首要死因是糖尿病心肌病，其中Akt信号通路的改变起着重要作用。最近发现Inpp5f是Akt信号的负调节因子，但其在糖尿病心脏中的表达及功能在很大程度上尚不明确。在本研究中，我们发现，在链脲佐菌素（STZ）和高脂饮食（HFD）诱导的糖尿病小鼠模型中，Inpp5f的表达受胰岛素、血糖和血脂水平的协同调控。Inpp5f表达增加与心脏功能呈负相关。进一步研究表明，胰岛素以Sp1依赖的方式在转录水平激活Inpp5f，而增加的Inpp5f反过来降低Akt的磷酸化水平，从而形成一个负反馈环。在糖尿病状态下，这种负反馈发挥着保护作用。然而，高血糖和高血脂（这是未控制的糖尿病和2型糖尿病的特征）通过激活NF-κB增加Inpp5f的表达，削弱了这种保护性反馈。因此，我们的研究揭示了Inpp5f作为胰岛素信号的负反馈调节因子，在糖尿病中下调Inpp5f对心脏具有保护作用。高血糖和高血脂导致的Inpp5f表达增加是糖尿病心肌病的一个重要介导因素，也是该疾病一个有前景的治疗靶点。
The leading cause of death in diabetic patients is diabetic cardiomyopathy, in which alteration of Akt signal plays an important role. Inpp5f is recently found to be a negative regulator of Akt signaling, while its expression and function in diabetic heart is largely unknown. In this study, we found that in both the streptozotocin (STZ) and high fat diet (HFD) induced diabetic mouse models, Inpp5f expression was coordinately regulated by insulin, blood glucose and lipid levels. Increased Inpp5f was inversely correlated with the cardiac function. Further studies revealed that Insulin transcriptionally activated Inpp5f in an Sp1 dependent manner and increased Inpp5f in turn reduced the phosphorylation of Akt, forming a negative feedback loop. The negative feedback plays a protective role under diabetic condition. However, high blood glucose and lipid, which are characteristics of uncontrolled diabetes and type 2 diabetes, increased Inpp5f expression through activation of NF-κB, blunts the protective feedback. Thus, our study has revealed that Inpp5f provides as a negative feedback regulator of insulin signaling and downregulation of Inpp5f in diabetes is cardioprotective. Increased Inpp5f by hyperglycemia and hyperlipidemia is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease.