Unique Ability of Troglitazone to Up-Regulate Peroxisome Proliferator-Activated Receptor-γ Expression in Hepatocytes

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Abstract
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) 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-gamma. In the present study, we examined the mechanism whereby this induction occurs by specifically addressing whether potentiation of the transactivation function of PPAR-gamma 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-gamma, while rosiglitazone, englitazone, and ciglitazone were without effect. Similarly, the prostaglandin metabolite 15-deoxy-Delta(12,14)-prostaglandin J(2) 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 alpha-tocopherol and observed that it induced PPAR-gamma expression in a dose-dependent fashion. Finally, we found that mice fed troglitazone as a dietary admixture displayed an up-regulation of hepatic PPAR-gamma 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-gamma does not alone account for the induction of expression of PPAR-gamma by troglitazone, and 2) an antioxidant-related mechanism may be involved.