Receptor-independent actions of PPAR thiazolidinedione agonists: Is mitochondrial function the key?

Article ID	Journal	Published Year	Pages	File Type
9001910	Biochemical Pharmacology	2005	12 Pages	PDF

Abstract

Agonists of the peroxisome proliferator activated receptor gamma (PPARÎ³) are currently used for treatment of type 2 diabetes due to their insulin sensitizing and glucose metabolism stabilizing effects. More recently some of these same agonists were shown to exert anti-inflammatory and anti-proliferative effects as well. Although PPARÎ³ agonists can operate via receptor-mediated events occurring at the genomic level, thereby causing long lasting changes in gene expression patterns, recent studies demonstrate non-genomic as well as genomic actions, and receptor-dependent as well as receptor-independent effects of the thiazolidinedione (TZD) class of PPARÎ³ agonists. In this review we will summarize data describing some of these novel, receptor independent actions of TZDs, review evidence that TZDs directly influence mitochondrial function, and attempt to reconcile how changes in mitochondrial function could contribute to other receptor-independent actions of these drugs.

Keywords

CPT1 ERK HSR NOS PPARγ Hsp IκB ΔΨm CBP IKK Gadd45 EGR-1 GLUT NOS2 VCAM-1 CREB AP1 TZD PDH PGC1α NAG-1 inhibitor of nuclear factor kappa B PGJ2 Prostaglandin J2 c-Jun NH2-terminal protein kinase TNF TROG cyclic AMP-responsive element binding protein growth arrest and DNA damage-inducible gene PPARγ coactivator 1α AMPK LPS Jnk FFA AICAR COX AUC DMSO IκB kinase malonyl-CoA decarboxylase MAPK NFκB pIO Small interfering RNA ROS siRNA adenosine 5′-monophosphate-activated protein kinase cyclooxygenase PPRE Fatty acid Free fatty acid insulin interferon IFN interleukin Troglitazone Thiazolidinedione Glucose transporter CNS Dimethyl sulfoxide ROSI rosiglitazone Cytokines central nervous system extracellular signal regulated kinase tumor necrosis factor nuclear factor kappa B Human leukemia lipopolysaccharide Metabolism area under the curve vascular cell adhesion molecule-1 MitoNEET Mitochondria Nitric oxide nitric oxide synthase Stress response early growth response-1 Heat shock response Mitochondrial membrane potential CREB-binding protein Heat shock protein activator protein 1 Protein kinase prostaglandin pyruvate dehydrogenase mitogen-activated protein kinases Pioglitazone Glucose Reactive oxygen species Peroxisome proliferator activated receptor gamma