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CYP2E1 impairs GLUT4 gene expression and function: NRF2 as a possible mediator.

M Armoni1, C Harel1, M Ramdas1

  • 1Institute of Endocrinology, Diabetes and Metabolism, Rambam Medical Center, and Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme
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Summary

Cytochrome P450 2E1 (CYP2E1) impairs glucose transporter 4 (GLUT4) function and expression in cells, contributing to insulin resistance. This occurs via the transcription factor NRF2, highlighting CYP2E1 and NRF2 as key regulators.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Impaired glucose transporter 4 (GLUT4) function and expression are hallmarks of insulin resistance in diabetes and obesity.
  • Cytochrome P450 isoform 2E1 (CYP2E1) is known to induce oxidative stress and impair insulin action.

Purpose of the Study:

  • To investigate the molecular mechanisms by which CYP2E1 affects GLUT4 gene expression and function in adipose and muscle cells.
  • To elucidate the role of CYP2E1 in insulin resistance at the cellular level.

Main Methods:

  • Overexpression and silencing of CYP2E1 in L6 muscle cells and primary rat adipose cells.
  • Assays for insulin-stimulated glucose uptake, 2-deoxyglucose uptake, and GLUT4 translocation.
  • Analysis of GLUT4 gene expression at promoter and mRNA levels.
  • Chromatin immunoprecipitation (ChIP) assays and promoter analysis.
  • Investigation of the role of transcription factor NF-E2-related factor 2 (NRF2).

Main Results:

  • CYP2E1 overexpression inhibited insulin-stimulated GLUT4 translocation and glucose uptake in L6 cells, an effect partially blocked by vitamin E.
  • CYP2E1 suppressed GLUT4 gene expression in L6 and adipose cells, while CYP2E1 silencing increased it.
  • CYP2E1-induced suppression of GLUT4 was mediated by NRF2, involving direct NRF2 binding to the GLUT4 promoter.
  • Antioxidants and a CYP2E1 inhibitor blocked CYP2E1's suppressive effect on GLUT4 expression.

Conclusions:

  • CYP2E1 negatively regulates GLUT4 gene expression and function in insulin-sensitive cells through an NRF2-dependent mechanism.
  • CYP2E1 and NRF2 act as key negative regulators of GLUT4 in cellular models of insulin resistance.
  • These findings provide insights into the molecular pathways linking CYP2E1 to impaired glucose metabolism.