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Oleic and linoleic fatty acids downregulate Slc2a4/GLUT4 expression via NFKB and SREBP1 in skeletal muscle cells

Ana Cláudia Poletto1, Daniela Tomie Furuya1, Aline David-Silva1

  • 1Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Molecular and Cellular Endocrinology
|December 9, 2014
PubMed

Insights

Oleic acid (OA) and linoleic acid (LA) reduce skeletal muscle glucose transporter type 4 (GLUT4) expression. This occurs via decreased SREBP1 and increased NF-kappa B activity, potentially contributing to insulin resistance.

Area of Science:

  • Molecular Biology
  • Cellular Metabolism
  • Endocrinology

Background:

  • Oleic acid (OA) and linoleic acid (LA) are fatty acids potentially influencing insulin sensitivity.
  • The Slc2a4 gene, encoding glucose transporter type 4 (GLUT4) protein, is crucial for glucose uptake in skeletal muscle.
  • Dysregulation of GLUT4 expression is implicated in insulin resistance.

Purpose of the Study:

  • To investigate the impact of OA and LA on Slc2a4/GLUT4 expression in L6 muscle cells.
  • To identify potential transcriptional regulators affected by OA and LA.

Main Methods:

  • L6 muscle cells were treated with varying concentrations of OA and LA (50-400 µM).
  • Slc2a4/GLUT4 expression levels were measured.
  • Binding activities of transcription factors, including sterol-regulatory-element-binding-protein-1 (SREBP1) and nuclear factor-kappa B (NF-kappa B), were assessed.
  • Phosphorylation of inhibitors of nuclear-factor-kappa-B-kinase alpha/beta was analyzed.

Main Results:

  • OA and LA significantly decreased Slc2a4/GLUT4 expression in a dose-dependent manner (up to ~50%).
  • OA and LA reduced the binding activity of SREBP1 enhancer (~50%).
  • OA and LA increased nuclear protein binding to the NF-kappa B site (repressor) (~30%) and induced significant phosphorylation of IKK alpha/beta (150-300%).

Conclusions:

  • Oleic acid and linoleic acid are potent inhibitors of Slc2a4/GLUT4 expression in muscle cells.
  • This inhibition is mediated by reduced SREBP1 activity and enhanced NF-kappa B transcriptional activity.
  • These molecular changes may contribute to the pathophysiology of insulin resistance associated with fatty acid dysregulation.
Keywords:
Electrophoretic mobility shift assayInsulin resistanceLXR-αPPAR-γTranscription factorsUnsaturated fatty acid

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