CCAAT/enhancer-binding Protein Alpha Mediates Induction of Hepatic Phosphoenolpyruvate Carboxykinase by P38 Mitogen-activated Protein Kinase

Excessive hepatic gluconeogenesis and glucose production are important contributors to hyperglycemia in both type 1 and type 2 diabetes. In diabetic humans and animal models, elevated levels of p38 mitogen-activated protein kinase (p38) are observed in several tissues. Our study shows that activity of p38 is significantly elevated in livers of db/db or streptozocin-induced type 1 diabetic mice. Using cultured hepatoma cells, we find that activation of p38 enhances expression of hepatic gluconeogenic gene phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, our studies demonstrate that activation of p38 stimulates phosphorylation of CCAAT/enhancer-binding protein alpha (C/EBPalpha) at serine 21 and increases its transactivation activity in the context of PEPCK gene transcription. Our results indicate that C/EBPalpha mediates p38-stimulated PEPCK transcription in liver cells.