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PTP1B inhibitor improves both insulin resistance and lipid abnormalities in vivo and in vitro

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Abstract

PTP1B is a negative regulator of insulin signaling pathway. This study investigated the effects of compound CCF06240, a PTP1B inhibitor, on insulin sensitivity and lipid metabolic abnormalities in vivo and in vitro, respectively. The insulin resistant IRM mouse model was induced by HFD. The responses to insulin were determined by OGTT, ITT, and hyperinsulinemic–euglycemic clamp test. The body weight and the levels of serum TC and TG were measured to estimate the lipid metabolism in vivo. Recombinant human GST-PTP1B protein was used to measure the inhibition of CCF06240 on PTP1B activity. The hepatocyte lipid accumulation was induced by high concentrations of FFA and insulin in HepG2 cells, and evaluated by the Oil Red O method. In IRM mice, the insulin resistance was improved; the body weight and the levels of TC and TG were also reduced by oral CCF06240 administration. In lipid accumulated model cells, CCF06240 was found to reverse the increased PTP1B activity, enhance the insulin-induced tyrosine phosphorylation in insulin signaling pathway, attenuate the FFA-insulin-induced cellular lipid accumulation, and down-regulate the expressions of genes related fatty acid synthesis. These results demonstrated that the PTP1B inhibitor, compound CCF06240, could increase insulin sensitivity through the regulation of insulin signaling pathway, and decrease FFA-insulin-induced hepatocytes lipid accumulation by reducing fatty acid syntheses.

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Abbreviations

ACCβ:

Acetyl coenzyme A carboxylase β

AUC:

Area under curve

Con:

Control

FAS:

Fatty acid synthase

GIR:

Glucose infusion rate

HFD:

High-fat-diet

ITT:

Insulin tolerant test

IR:

Insulin receptor

IRM:

Insulin resistance model

IRS:

Insulin receptor substrate

OGTT:

Oral glucose tolerant test

PTP1B:

Protein tyrosine phosphatase 1B

pNPP:

p-Nitrophonyl phosphate

Rosi:

Rosiglitazone

RT-PCR:

Reverse transcription polymerase chain reaction

SREBPs:

Sterol response element-binding proteins

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Acknowledgments

The authors thank Dr. Maegawa in Shiga Medical University (Japan) for the HepG2 cells and Servier Company (France) for the PTP1B plasmid as the kindly gifts. The authors also thank National Science & Technology Major Project (No. 2009ZX09103-432, 2009ZX09303-003) and Natural Sciences Funds of Inner Mongolian Autonomous Region (No. 20080404Zd31) for the financial support.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, 1, Xian Nong Tan street, Beijing, 100050, China

    Yi-ming Ma, Rong-ya Tao, Qian Liu, Juan Li, Jin-ying Tian, Xiao-lin Zhang, Zhi-yan Xiao & Fei Ye

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  1. Yi-ming Ma
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  2. Rong-ya Tao
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  3. Qian Liu
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  4. Juan Li
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  5. Jin-ying Tian
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  6. Xiao-lin Zhang
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  7. Zhi-yan Xiao
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  8. Fei Ye
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Correspondence to Fei Ye.

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Ma, Ym., Tao, Ry., Liu, Q. et al. PTP1B inhibitor improves both insulin resistance and lipid abnormalities in vivo and in vitro. Mol Cell Biochem 357, 65–72 (2011). https://doi.org/10.1007/s11010-011-0876-4

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  • DOI: https://doi.org/10.1007/s11010-011-0876-4

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