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  • Huntingtin-associated protein 1 plays an essential role in the pathogenesis of type 2 diabetes by regulating the translocation of GLUT4 in mouse adipocytes

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Pathophysiology/complications
Huntingtin-associated protein 1 plays an essential role in the pathogenesis of type 2 diabetes by regulating the translocation of GLUT4 in mouse adipocytes
  1. Yan-Ju Gong1,
  2. Ying Feng1,
  3. Yuan-Yuan Cao1,
  4. Jia Zhao1,
  5. Wei Wu2,
  6. Ya-Yun Zheng1,
  7. Jia-Rui Wu1,
  8. Xin Li3,
  9. Gui-Zhi Yang1,
  10. Xue Zhou1
  1. 1Department of Histology, Embryology and Neurobiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China
  2. 2Institute of Biology, National Institute of Measurement and Testing Technology, Chengdu, Sichuan, China
  3. 3Department of Pathophysiology, School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
  1. Correspondence to Professor Xue Zhou; zhouxue7239{at}163.com; Professor Gui-Zhi Yang; ygzxky{at}163.com

Abstract

Objective Glucose disposal by insulin-responsive tissues maintains the body glucose homeostasis and insulin resistance leads to a risk of developing type 2 diabetes (T2DM). Insulin stimulates the translocation of glucose transporter isoform 4 (GLUT4) vesicles from intracellular compartments to the plasma membrane to facilitate glucose uptake. However, the underlying mechanisms of GLUT4 vesicle translocation are not well defined. Here we show the role of huntingtin-associated protein 1 (HAP1) in GLUT4 translocation in adipocytes and the pathogenesis of T2DM.

Research design and methods The parameters for glucose metabolism including body weight, glucose tolerance and insulin tolerance were assessed in wild-type (WT) and Hap1+/- mice. HAP1 protein expression was verified in adipose tissue. Hap1 mRNA and protein expression was monitored in adipose tissue of high-fat diet (HFD)-induced diabetic mice. Insulin-stimulated GLUT4 vesicle translocation and glucose uptake were detected using immunofluorescence techniques and quantified in primary adipocytes from Hap1-/- mice. The interaction between HAP1 and GLUT4 was assessed by immunofluorescence colocalization and co-immunoprecipitation in HEK293 cells and adipose tissue. The role of sortilin in HAP1 and GLUT4 interaction was approved by co-immunoprecipitation and RNA interference.

Results The expression of Hap1 mRNA and protein was detected in WT mouse adipose tissue and downregulated in adipose tissue of HFD-induced diabetic mice. Hap1+/- mice exhibited increased body weight, pronounced glucose tolerance and significant insulin intolerance compared with the WT mice. HAP1 colocalized with GLUT4 in mouse adipocytes and cotransfected HEK293 cells. Furthermore, the insulin-stimulated GLUT4 vesicle translocation and glucose uptake were defective in Hap1-/- adipocytes. Finally, sortilin mediated the interaction of HAP1 and GLUT4.

Conclusions Our study showed that HAP1 formed a protein complex with GLUT4 and sortilin, and played a critical role in insulin-stimulated GLUT4 translocation in adipocytes. Its downregulation may contribute to the pathogenesis of diabetes.

  • type 2 diabetes
  • GLUT4
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2020-001199

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    Footnotes

    • Y-JG and YF contributed equally.

    • G-ZY and XZ contributed equally.

    • Contributors YF, G-ZY and XZ conceived the studies; Y-JG, YF, G-ZY and XZ provided critical input to study design, interpretation/discussion of results; Y-JG, YF, Y-YC, JZ, WW, Y-YZ, J-RW and XL acquired, analyzed and interpreted data; Y-JG wrote the manuscript. All authors read and approved the final manuscript.

    • Funding This work was supported by the Office of Science and Technology of Chengdu (grant no: 2016-HM01-00514-SF).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval All experiments were performed in accordance with the guidelines on the care and use of animals for research purposes by the Institutional Animal Care and Use Committee of Sichuan University, and all the procedures were approved by the Institutional Animal Care and Use Committee of Sichuan University.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information.