Glucose-mediated tyrosine nitration in adipocytes: targets and consequences.
Hyperglycemia, a key factor in insulin resistance and diabetic pathology, is associated with cellular oxidative stress that promotes oxidative protein modifications. We report that protein nitration is responsive to changes in glucose concentrations in 3T3-L1 adipocytes. Alterations in the extent of tyrosine nitration as well as the cellular nitroproteome profile correlated tightly with changing glucose concentrations. The target proteins we identified are involved in fatty acid binding, cell signaling, protein folding, energy metabolism, antioxidant capacity, and membrane permeability. The nitration of adipocyte fatty acid binding protein (FABP4) at Tyr19 decreases, similar to phosphorylation, the binding of palmitic acid to the fatty acid-free protein. This potentially alters intracellular fatty acid transport, nuclear translocation of FABP4, and agonism of PPAR gamma. Our results suggest that protein tyrosine nitration may be a factor in obesity, insulin resistance, and the pathogenesis of diabetes.
Koeck
Thomas
T
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44118, USA. koeckt@ccf.org
Willard
Belinda
B
Crabb
John W
JW
Kinter
Mike
M
Stuehr
Dennis J
DJ
Aulak
Kulwant S
KS
D041721:3T3-L1 Cells; D021581:Active Transport, Cell Nucleus; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009566:Nitrates / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D009566:Nitrates; D019308:Palmitic Acid; D014443:Tyrosine; D005947:Glucose