Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression bytroglitazone: a peroxisome proliferator-activated receptor-gamma (PPAR gamma)-independent, antioxidant-related mechanism

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gl uconeogenesis. Enhanced expression of the PEPCK gene in liver is present in most models of diabetes, and is thought to contribute to the increased hep atic glucose output seen in this disease. Recently, we showed that troglita zone, the first thiazolidinedione (TZD) used clinically, inhibits expressio n of the PEPCK gene in isolated hepatocytes. We have pursued the molecular mechanism whereby troglitazone exerts this inhibition. TZDs are known to bi nd and activate peroxisome proliferator-activated receptor-gamma (PPAR gamm a), a nuclear receptor, which regulates expression of target genes. Initial ly, we examined the abilities of three other TZDs (rosiglitazone, englitazo ne, and ciglitazone) to inhibit expression of the PEPCK gene. Despite the f act that these agents are ligands for PPAR-gamma, they displayed little if any inhibitory activity on the expression of this gene. GW1929 [N-(2-benzoy l phenyl)-1-tyrosine], another potent PPAR-gamma ligand that is unrelated s tructurally to TZDs, had no inhibitory effect on PEPCK gene expression, whi le a natural PPAR gamma ligand, the prostaglandin metabolite 15-PGJ(2) (15- deoxy-Delta (12,14)-prostaglandin J(2)), displayed only modest inhibitory a ctivity. Treatment of hepatocytes with ligands for other isoforms of PPAR a lso had no significant effect on PEPCK gene expression. Troglitazone has an a-tocopherol (vitamin E) moiety that is not present in other TZDs, and tre atment of hepatocytes with vitamin E led to an inhibition of PEPCK gene exp ression. These observations support the conclusion that troglitazone inhibi ts the expression of the PEPCK gene by a PPAR gamma -independent, antioxida nt-related mechanism. (C) 2001 Elsevier Science Inc. All rights reserved.