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Thioredoxin-interacting protein: a critical link between autophagy disorders and pancreatic β-cell dysfunction

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Abstract

Thioredoxin-interacting protein (TXNIP) is a known important regulatory protein of islet β-cell biology and function, but the detailed mechanism is not clear. Autophagy plays a pivotal role in maintaining cellular homoeostasis. This study aimed to elucidate the influence of TXNIP on the autophagy of β-cell. In this study, C57BL/6 mice and TXNIP−/− mice were fed with a standard diet (SD) or a high-fat and high-sugar diet (HFSD), and then we analysed biochemical and autophagy related indexes in the mice. We infected MIN6 cells with LV-TXNIP and siRNA TXNIP, then the cells were treated with free fatty acid (FFA), autophagic activator rapamycin (RAP), inhibitors of autophagy chloroquine (CQ) and bafilomycin A1(BAF), finally, we examined the changes of autophagy in MIN6 cells. The results showed that HFSD led to β-cell dysfunction and autophagy dysregulation, which was improved by TXNIP knockout in mice. In vitro experiments, TXNIP gene silencing enhanced LC3B-I conversion to LC3B-II, reduced the protein level of P62, decreased autophagosome accumulation induced by FFA treatment, increased the glucose-stimulated insulin secretion (GSIS) and autophagic flux inhibited by treatment with CQ. TXNIP overexpression induced upregulation of LC3B-I, LC3B-II and P62, accentuating the increase in autophagy and organelle destruction induced by FFA, and exacerbated the effect of BAF on the accumulation of autophagy proteins. Increasing TXNIP levels reduced GSIS, which was reversed by treatment with RAP. In summary, our study suggested that TXNIP is a critical link between autophagy disorders and pancreatic β-cell dysfunction.

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Funding

This work was supported by research grants from the National Natural Science Foundation of China (81370467).

Author contributions

W.Z.D. collected the data, interpreted the data and wrote the paper. D.F.L. designed the study, interpreted the data and edited the paper. X.F.G. designed the study and interpreted the data. Y.L., Z.Y.R. and W.Z.D. performed the experiments, interpreted the data and edited the paper. Q.R.H. edited the paper and performed some of the experiments. Y.J.J., Y.J.L. and W.W.Z. performed some of the experiments.

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  1. These authors contributed equally: Wenzhen Deng, Yang Li, Ziyu Ren.

Authors and Affiliations

  1. Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, 400010, Chongqing, China

    Wenzhen Deng, Yang Li, Ziyu Ren, Qirui He, Yanjun Jia, Yongjian Liu, Weiwei Zhang & Dongfang Liu

  2. Department of Endocrinology, Qianjiang Central Hospital of Chongqing, 409000, Chongqing, China

    Wenzhen Deng

  3. Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, 610072, Chengdu, China

    Xianfeng Gan

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  1. Wenzhen Deng
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Deng, W., Li, Y., Ren, Z. et al. Thioredoxin-interacting protein: a critical link between autophagy disorders and pancreatic β-cell dysfunction. Endocrine 70, 526–537 (2020). https://doi.org/10.1007/s12020-020-02471-6

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