Down Regulation of Adipose Glutathione S-Transferase Leads to Increased Protein Carbonylation, Oxidative Stress and Mitochondrial Dysfunction

  1. Jessica M. Curtis1,
  2. Paul A. Grimsrud1,
  3. Wendy S. Wright1,
  4. Xin Xu2,
  5. Rocio E. Foncea1,
  6. David W. Graham1,
  7. Jonathan R. Brestoff1,
  8. Brian M. Wiczer1,
  9. Olga Ilkayeva4,
  10. Katherine Cianflone3,
  11. Deborah E. Muoio4,5,
  12. Edgar A. Arriaga2 and
  13. David A. Bernlohr (bernl001{at}umn.edu)1
  1. From the Departments of 1Biochemistry, Molecular Biology and Biophysics and
  2. 2Chemistry, The University of Minnesota, Minneapolis, MN 55455
  3. 3McGill University Health Centre, Montreal, Canada
  4. 4Sarah W. Stedman Nutrition and Metabolism Center and
  5. 5Departments of Medicine and Pharmacology & Cancer Biology, Duke University, Durham, NC, 27704

Abstract

Objective - Peripheral insulin resistance is linked to an increase in reactive oxygen species (ROS) leading in part to the production of reactive lipid aldehydes that modify the side chains of protein amino acids in a reaction termed protein carbonylation. The primary enzymatic method for lipid aldehyde detoxification is via glutathione S-transferase A4 dependent glutathionylation. The objective of this study was to evaluate the expression of GSTA4 and the role(s) of protein carbonylation in adipocyte function.

Research Design And Methods – GSTA4 silenced 3T3-L1 adipocytes and GSTA4 null mice were evaluated for metabolic processes, mitochondrial function and reactive oxygen species production. GSTA4 expression in human obesity was evaluated using microarray analysis.

Results - GSTA4 expression is selectively down regulated in adipose tissue of obese insulin resistant C57BL/6J mice and in human obesity-linked insulin resistance. TNFα treatment of 3T3-L1 adipocytes decreased GSTA4 expression and silencing GSTA4 mRNA in cultured adipocytes resulted in increased protein carbonylation, increased mitochondrial ROS, dysfunctional state 3 respiration and altered glucose transport and lipolysis. Mitochondrial function in adipocytes of lean or obese GSTA4 null mice were significantly compromised compared to wild type controls and was accompanied by an increase in superoxide anion.

Conclusions - These results indicate that down regulation of GSTA4 in adipose tissue leads to increased protein carbonylation, ROS production and mitochondrial dysfunction and may contribute to the development of insulin resistance and type 2 diabetes.

Footnotes

    • Received July 28, 2009.
    • Accepted January 27, 2010.

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