Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions.
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.
Schopfer
Francisco J
FJ
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Cole
Marsha P
MP
Groeger
Alison L
AL
Chen
Chen-Shan
CS
Khoo
Nicholas K H
NK
Woodcock
Steven R
SR
Golin-Bisello
Franca
F
Motanya
U Nkiru
UN
Li
Yong
Y
Zhang
Jifeng
J
Garcia-Barrio
Minerva T
MT
Rudolph
Tanja K
TK
Rudolph
Volker
V
Bonacci
Gustavo
G
Baker
Paul R S
PR
Xu
H Eric
HE
Batthyany
Carlos I
CI
Chen
Y Eugene
YE
Hallis
Tina M
TM
Freeman
Bruce A
BA
D041721:3T3-L1 Cells; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D008024:Ligands; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology*; D019301:Oleic Acid / Q000737:chemistry / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000494:pharmacology
D001786:Blood Glucose; D017931:DNA Primers; D005231:Fatty Acids, Unsaturated; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D009574:Nitro Compounds; D047495:PPAR gamma; D011994:Recombinant Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019301:Oleic Acid