Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions
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Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions. / 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.
in: J BIOL CHEM, Jahrgang 285, Nr. 16, 16.04.2010, S. 12321-12333.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions
AU - Schopfer, Francisco J
AU - Cole, Marsha P
AU - Groeger, Alison L
AU - Chen, Chen-Shan
AU - Khoo, Nicholas K H
AU - Woodcock, Steven R
AU - Golin-Bisello, Franca
AU - Motanya, U Nkiru
AU - Li, Yong
AU - Zhang, Jifeng
AU - Garcia-Barrio, Minerva T
AU - Rudolph, Tanja K
AU - Rudolph, Volker
AU - Bonacci, Gustavo
AU - Baker, Paul R S
AU - Xu, H Eric
AU - Batthyany, Carlos I
AU - Chen, Y Eugene
AU - Hallis, Tina M
AU - Freeman, Bruce A
PY - 2010/4/16
Y1 - 2010/4/16
N2 - The peroxisome proliferator-activated receptor-gamma (PPARgamma) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARgamma 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 PPARgamma ligands are intermediates of lipid metabolism and oxidation that bind PPARgamma with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO(2)-FA) are endogenous products of nitric oxide ((*)NO) and nitrite (NO(2)(-))-mediated redox reactions that activate PPARgamma at nanomolar concentrations. We report that NO(2)-FA act as partial agonists of PPARgamma and covalently bind PPARgamma at Cys-285 via Michael addition. NO(2)-FA show selective PPARgamma modulator characteristics by inducing coregulator protein interactions, PPARgamma-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 NO(2)-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.
AB - The peroxisome proliferator-activated receptor-gamma (PPARgamma) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARgamma 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 PPARgamma ligands are intermediates of lipid metabolism and oxidation that bind PPARgamma with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO(2)-FA) are endogenous products of nitric oxide ((*)NO) and nitrite (NO(2)(-))-mediated redox reactions that activate PPARgamma at nanomolar concentrations. We report that NO(2)-FA act as partial agonists of PPARgamma and covalently bind PPARgamma at Cys-285 via Michael addition. NO(2)-FA show selective PPARgamma modulator characteristics by inducing coregulator protein interactions, PPARgamma-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 NO(2)-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.
KW - 3T3-L1 Cells
KW - Amino Acid Sequence
KW - Amino Acid Substitution
KW - Animals
KW - Base Sequence
KW - Blood Glucose/metabolism
KW - Cell Line
KW - DNA Primers/metabolism
KW - Diabetes Mellitus/drug therapy
KW - Fatty Acids, Unsaturated/chemistry
KW - Humans
KW - Hypoglycemic Agents/chemistry
KW - In Vitro Techniques
KW - Insulin/blood
KW - Ligands
KW - Lipid Metabolism
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Obese
KW - Molecular Sequence Data
KW - Mutagenesis, Site-Directed
KW - Nitro Compounds/chemistry
KW - Oleic Acid/chemistry
KW - PPAR gamma/agonists
KW - Protein Binding
KW - Protein Processing, Post-Translational
KW - Protein Structure, Tertiary
KW - Recombinant Proteins/chemistry
KW - Rosiglitazone
KW - Signal Transduction
KW - Tandem Mass Spectrometry
KW - Thiazolidinediones/pharmacology
U2 - 10.1074/jbc.M109.091512
DO - 10.1074/jbc.M109.091512
M3 - SCORING: Journal article
C2 - 20097754
VL - 285
SP - 12321
EP - 12333
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 16
ER -