Oxidative stress induces phosphoenolpyruvate carboxykinase expression in H4IIE cells.
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 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 mitogen-activated 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.
Ito
Yoshiaki
Y
Food and Health Science, Faculty of Agriculture, Iwate University, Morioka, Iwate, Japan. yito@iwate-u.ac.jp
Oumi
Saori
S
Nagasawa
Takashi
T
Nishizawa
Naoyuki
N
D000818:Animals; D015152:Blotting, Northern; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D005290:Ferric Compounds / Q000494:pharmacology; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D010545:Peroxides / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005290:Ferric Compounds; D007093:Imidazoles; D010545:Peroxides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D019328:Buthionine Sulfoximine; D048051:p38 Mitogen-Activated Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose; D009571:Nitrilotriacetic Acid; C093642:SB 203580; C020326:ferric nitrilotriacetate