Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart.

Danna Bai,Yongfeng Sun,Qing Xia,Xuedong Liu,Yingmei Zhang,Lijun Yuan,Haichang Wang,Yajun Zhang,Mingzhi Shen

doi:10.1038/srep22068

Abstract

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.

Highlights

Characterized as a new member of polyphosphoinositide phosphatases
We examined the expression of Inpp5f in two established experimental models of diabetes: Type 1 induced by STZ and Type 2 induced by high-fat diet (HFD)
Treatment of insulin in serum starved H9C2 cells dose dependently increased Inpp5f expression at Insulin, high glucose and FFA increase Inpp5f expression. (A) Serum starved H9C2 cells were treated with insulin at the indicated concentrations, and Western blot assay revealed a dose dependent upregulation of Inpp5f at protein level

Summary

Introduction

Characterized as a new member of polyphosphoinositide phosphatases. Accumulating evidence demonstrates that Inpp5f can degrade both phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2 [PIP2]) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns[3,4,5]P3 [PIP3]) by removing the 5′ phosphate from the inositol ring and inhibit Akt signaling[14,15,16,17]. The study by Zhu W et al has revealed that Inpp5f knockout mice are sensitive to hypertrophy, while Inpp5f transgenic mice are resistant to hypertrophy[18]. All of these data suggest that Inpp5f is a functionally important endogenous modulator of Akt signal and might plays an important role in response to physiological and pathological stimuli. Whether Inpp5f plays a role in the cardiomyopathy via fine-tuning Insulin/PI3K/PKB/Akt pathway in the context of diabetes has not been determined. By using the cell culture model, we explored the mechanism how Inpp5f regulates the Insulin/PI3K/PKB/Akt pathway and glucose uptake in the context of diabetes. Down-regulation of Inpp5f in response of decreased insulin signaling activity rescues Akt activity in a negative feedback manner and is cardioprotective in the context of diabetes, while uncontrolled hyperglycemia and hyperlipidemia blocks the protective feedback through upregulating Inpp5f

Methods

Results

Conclusion