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Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by troglitazone: a peroxisome proliferator-activated receptor-γ (PPARγ)-independent, antioxidant-related mechanism11Abbreviations: BADGE, bisphenol A diglycidyl ether; DCF, dichlorofluorescein; DCFH, 5- (and 6-)carboxy-2′,7′-dichlorodihydrofluorescein; PEPCK, phosphoenolpyruvate carboxykinase; 15-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; PPAR, peroxisome proliferator-activated receptor; RPPO, ribosomal phosphoprotein PO; TZD…

2001; Elsevier BV; Volume: 62; Issue: 8 Linguagem: Inglês

10.1016/s0006-2952(01)00764-x

1873-2968

Gerald F. Davies, Ramji L. Khandelwal, Lingyun Wu, B. H. J. Juurlink, William J. Roesler,

Adipose Tissue and Metabolism

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis. Enhanced expression of the PEPCK gene in liver is present in most models of diabetes, and is thought to contribute to the increased hepatic glucose output seen in this disease. Recently, we showed that troglitazone, the first thiazolidinedione (TZD) used clinically, inhibits expression of the PEPCK gene in isolated hepatocytes. We have pursued the molecular mechanism whereby troglitazone exerts this inhibition. TZDs are known to bind and activate peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, which regulates expression of target genes. Initially, we examined the abilities of three other TZDs (rosiglitazone, englitazone, and ciglitazone) to inhibit expression of the PEPCK gene. Despite the fact that these agents are ligands for PPARγ, they displayed little if any inhibitory activity on the expression of this gene. GW1929 [N-(2-benzoyl phenyl)-l-tyrosine], another potent PPARγ ligand that is unrelated structurally to TZDs, had no inhibitory effect on PEPCK gene expression, while a natural PPARγ ligand, the prostaglandin metabolite 15-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2), displayed only modest inhibitory activity. Treatment of hepatocytes with ligands for other isoforms of PPAR also had no significant effect on PEPCK gene expression. Troglitazone has an α-tocopherol (vitamin E) moiety that is not present in other TZDs, and treatment of hepatocytes with vitamin E led to an inhibition of PEPCK gene expression. These observations support the conclusion that troglitazone inhibits the expression of the PEPCK gene by a PPARγ-independent, antioxidant-related mechanism.