TY - JOUR T1 - Unique Ability of Troglitazone to Up-Regulate Peroxisome Proliferator-Activated Receptor-γ Expression in Hepatocytes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 72 LP - 77 DO - 10.1124/jpet.300.1.72 VL - 300 IS - 1 AU - Gerald F. Davies AU - Pamela J. McFie AU - Ramji L. Khandelwal AU - William J. Roesler Y1 - 2002/01/01 UR - http://jpet.aspetjournals.org/content/300/1/72.abstract N2 - Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by the binding of an appropriate ligand. Several studies have demonstrated that certain ligands can also induce the expression of PPAR-γ. In the present study, we examined the mechanism whereby this induction occurs by specifically addressing whether potentiation of the transactivation function of PPAR-γ per se leads to induction of expression. We observed that thiazolidinediones, a group of insulin-sensitizing drugs, had differential effects, with troglitazone inducing protein levels of PPAR-γ, while rosiglitazone, englitazone, and ciglitazone were without effect. Similarly, the prostaglandin metabolite 15-deoxy-Δ12,14-prostaglandin J2 and the potent synthetic ligand GW1929 (N-(2-benzoyl phenyl)-l-tyrosine) also had no effect, as did ligands for other isoforms of PPAR. Since troglitazone has antioxidant properties, we also examined the effect of α-tocopherol and observed that it induced PPAR-γ expression in a dose-dependent fashion. Finally, we found that mice fed troglitazone as a dietary admixture displayed an up-regulation of hepatic PPAR-γ mRNA and protein, indicating that the mechanism of action is at the level of gene expression and not protein stability. These data indicate that 1) up-regulation of the transactivation function of PPAR-γ does not alone account for the induction of expression of PPAR-γ by troglitazone, and 2) an antioxidant-related mechanism may be involved. PPARperoxisome proliferator-activated receptorCATchloramphenicol acetyltransferase15-PGJ215-deoxy-Δ12,14-prostaglandin J2 LY171,8831-(2-hydroxy-3-propyl-4-(4-(1H-tetrazol-5-yl)butoxy)phenyl)ethaneWY14,6434-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acidETYA5,8,11,14-eicosatetraynoic acidPEPCKphosphoenolpyruvate carboxykinaseTZDthiazolidinedioneRPPOribosomal phosphoprotein PORXRretinoid X receptor ER -