Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids: SELECTIVE LIGAND ACTIVITY AND ANTI-DIABETIC SIGNALING ACTIONS

• Published in: The Journal of biological chemistry Vol. 285; no. 16; pp. 12321 - 12333
• Main Authors: Schopfer, Francisco J, Cole, Marsha P, Groeger, Alison L, Chen, Chen-Shan, Khoo, Nicholas K.H, Woodcock, Steven R, Golin-Bisello, Franca, Motanya, U. Nkiru, Li, Yong, Zhang, Jifeng, Garcia-Barrio, Minerva T, Rudolph, Tanja K, Rudolph, Volker, Bonacci, Gustavo, Baker, Paul R.S, Xu, H. Eric, Batthyany, Carlos I, Chen, Y. Eugene, Hallis, Tina M, Freeman, Bruce A
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 16.04.2010
• Subjects: 3T3-L1 Cells; Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; Blood Glucose - metabolism; Cell Line; Diabetes Mellitus - drug therapy; Diabetes Mellitus - metabolism; DNA Primers - metabolism; Fatty Acids, Unsaturated - chemistry; Fatty Acids, Unsaturated - pharmacology; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Insulin - blood; Ligands; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Bases of Disease; Molecular Sequence Data; Mutagenesis, Site-Directed; Nitro Compounds - chemistry; Nitro Compounds - pharmacology; Oleic Acid - chemistry; Oleic Acid - pharmacology; PPAR gamma - agonists; PPAR gamma - chemistry; PPAR gamma - genetics; PPAR gamma - metabolism; Protein Binding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rosiglitazone; Signal Transduction; Tandem Mass Spectrometry; Thiazolidinediones - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.091512

The peroxisome proliferator-activated receptor-γ (PPARγ) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARγ include lipids and anti-hyperglycemic drugs such as thiazolidinediones (TZDs). Recently, TZDs have raised concern after being linked with increased risk of peripheral edema, weight gain, and adverse cardiovascular events. Most reported endogenous PPARγ ligands are intermediates of lipid metabolism and oxidation that bind PPARγ with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO₂-FA) are endogenous products of nitric oxide ( NO) and nitrite (NO[Formula: see text])-mediated redox reactions that activate PPARγ at nanomolar concentrations. We report that NO₂-FA act as partial agonists of PPARγ and covalently bind PPARγ at Cys-285 via Michael addition. NO₂-FA show selective PPARγ modulator characteristics by inducing coregulator protein interactions, PPARγ-dependent expression of key target genes, and lipid accumulation is distinctively different from responses induced by the TZD rosiglitazone. Administration of this class of signaling mediators to ob/ob mice revealed that NO₂-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.