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TLR4 knockout can improve dysfunction of β-cell by rebalancing proteomics disorders in pancreas of obese rats

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Abstract

Purpose

Studies showed that TLR4 knockout (TLR4KO) could mitigate obesity and insulin resistance induced by high-fat diet in rats. In this study, we further investigated the effects of TLR4KO on islet function and pancreatic proteomics in obese rats by high-fat diet.

Methods

PA-induced lipotoxicity β-cells, SD and TLR4KO rats were used in this study. iTRAQ was used to screen out meaningful differential proteins.The protein expression level was evaluated by Western blotting; the cell apoptosis was detected by TUNEL assay.

Results

TLR4KO could reduce inflammatory and regulate body composition in obese rats, and improve β-cells function. The quantitative analysis of protein revealed that TLR4KO rebalanced proteomics disorders in pancreas of obese rats. In addition, the pathways involved in differential proteins were mainly metabolic pathways, arachidonic acid metabolism, ECM–receptor interaction, pancreatic secretion, PI3K-Akt signaling pathway, and FoxO signaling pathway. Further analysis of protein–protein interaction (PPI) revealed that Stk39 and Ass1 interacting through Mapk14-Ywhae were node proteins and participated in inflammatory response, carboxylic acid metabolic process, and small molecule metabolic process. In vitro experiments we confirmed that silencing TLR4 can inhibit PA-induced β-cell apoptosis, insulin secretion disorders, and increase Ass1 expression. While, overexpression of Ass1 in β-cell inhibited PA or LPS-induced β-cell damage.

Conclusions

Our study confirmed that TLR4KO could improve dysfunction of β-cell, and the underlying mechanism might be involved in ebalancing proteomics disorders in pancreas, affecting the expression of Ass1.

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Funding

This study was funded by Science and technology innovation joint fund project Fujian Province (grant numbers 2016Y9102), Grants from National Natural Science Foundation of China (grant numbers 81500632 and 81870572), Natural Science Foundation of Fujian Province (grant number 2019J01455 and 2015J01453), Fujian Province Higher Education Institute New Century Research Project (grant number 2018B049) and Medical Innovation Fund Project of Fujian Province (grant numbers 2018-CX-23).

Author contributions

S.Y., Z.J. and L. C. wrote manuscript; X.S. conducted the design of the study and reviewed/edited the drafts, and is guarantor; B.F. researched data and edited the drafts; L.L. and Y.Y. contributed to discussion.Y.L. supplied the western blot experiment of islet and participated in modification of the manuscript. X.S. and L.Y. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Author notes

  1. These authors contributed equally: Ling Cheng, Zhen Jiang

Authors and Affiliations

  1. From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China

    Sunjie Yan, Zhen Jiang, Ling Cheng, Youfen Lin, Beibei Fan, Liufen Luo, Yuanli Yan, Liyong Yang & Ximei Shen

  2. Diabetes Research Institute of Fujian Province, Fuzhou, 350005, Fujian, China

    Sunjie Yan, Liyong Yang & Ximei Shen

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  1. Sunjie Yan
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Correspondence to Ximei Shen.

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Yan, S., Jiang, Z., Cheng, L. et al. TLR4 knockout can improve dysfunction of β-cell by rebalancing proteomics disorders in pancreas of obese rats. Endocrine 67, 67–79 (2020). https://doi.org/10.1007/s12020-019-02106-5

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