Oxidative Stress Induces Phosphoenolpyruvate Carboxykinase Expression in H4IIE Cells

Yoshiaki ITO, Saori OUMI, Takashi NAGASAWA, Naoyuki NISHIZAWA
2006 Bioscience, biotechnology and biochemistry  
Oxidative stress is closely associated with diabetes and is a major cause of insulin resistance. Impairment of hepatic insulin action is thought to be responsible for perturbations in hepatic glucose metabolism. In this study, we found that oxidative stress is involved in the dysregulation of gene expression of phosphoenolpyruvate carboxykinase (PEPCK), a key gluconeogenic enzyme, by a mechanism independent of insulin. Elevation of oxidative stress by injection of ferric nitrilotriacetate in
more » ... ilotriacetate in rats increased the expression of hepatic PEPCK mRNA. To examine the direct action of oxidative stress on PEPCK expression, we treated H4IIE hepatoma cells with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. BSO increased intracellular oxidative stress and the expression of PEPCK mRNA. Inhibition of p38 mitogenactivated protein kinase (p38 MAP kinase), which mediates responses to oxidative stress, suppressed the induction of PEPCK mRNA by BSO. These results suggest that oxidative stress dysregulates hepatic PEPCK expression by an insulin-independent mechanism. Key words: diabetes; oxidative stress; phosphoenolpyruvate carboxykinase (PEPCK); p38 mitogen-activated protein kinase (p38 MAP kinase); gluconeogenesis Alterations in hepatic glucose metabolism play an important role in the development of the hyperglycemia associated with diabetic states. Increased gluconeogenesis is responsible for excess hepatic glucose output and contributes to both fasting hyperglycemia and exacerbated postprandial hyperglycemia. 1-4) Studies in animal models of type 2 diabetes and obesity suggest that phosphoenolpyruvate carboxykinase (PEPCK), a ratecontrolling gluconeogenic enzyme, contributes to this elevation of gluconeogenesis in that they show 2-to 3fold increases in PEPCK mRNA levels as compared to nondiabetic animals. 5,6) Also, transgenic mice that overexpress PEPCK display hyperglycemia. 7,8) These animals also show insulin resistance, suggesting that elevation of blood glucose impairs insulin action. There is considerable evidence that hyperglycemia results in the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress. 9) Accumulation of oxidative stress is involved not only in the development of diabetic complications but also in the progression of insulin resistance, because it interferes with insulin signaling. 10) Oxidative stress can activate the stress-activated signaling pathways, including p38 mitogen-activated protein (MAP) kinase, which modulate factors in the insulin signaling pathway. 11, 12)
doi:10.1271/bbb.60135 pmid:16960379 fatcat:ckozhxt4hfcfvoldzgxzbkkyce