Unique ability of troglitazone to up-regulate peroxisome proliferator-activated receptor-gamma expression in hepatocytes.
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.
Davies
Gerald F
GF
Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
McFie
Pamela J
PJ
Khandelwal
Ramji L
RL
Roesler
William J
WJ
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002839:Chromans / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D000077288:Troglitazone; D015854:Up-Regulation / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
D002839:Chromans; D007004:Hypoglycemic Agents; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014810:Vitamin E; D000077288:Troglitazone