C/EBP is AMP kinase sensitive and up-regulates PEPCK in response to ER stress in hepatoma cells. Academic Article uri icon

abstract

  • Diabetes and obesity are associated with activation of endoplasmic reticulum (ER) stress; however a direct link between ER stress and increased hepatic gluconeogenesis remains unclear. Here we show that ER stress triggers a significant increase in expression of CCAAT/enhancer-binding protein (C/EBP) and phosphorylated CREB together with reduced phospho-AMP-activated protein kinase (pAMPK) in hepatoma cells. ER stress contributed to transcriptional activation of the gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK) promoter in Huh7 and HepG2 cells via cAMP binding motif (CRE site). Chromatin immunoprecipitation assays demonstrate that C/EBP is recruited to the PEPCK promoter during ER stress and is reversed by pre-treatment with a JNK inhibitor that relieves ER stress. C/EBP but not pCREB was suppressed by the AMPK-activator AICAR or constitutively active AMPK, while dominant negative AMPK increased C/EBP expression. These data suggest that ER stress triggers suppression of AMPK while increasing C/EBP and pCREB expression which activates PEPCK gene transcription. Understanding how ER stress suppresses AMPK activation and increases C/EBP expression could lead to a potentially novel pathway for treatment of diabetes.

published proceedings

  • Mol Cell Endocrinol

author list (cited authors)

  • Choudhury, M., Qadri, I., Rahman, S. M., Schroeder-Gloeckler, J., Janssen, R. C., & Friedman, J. E.

citation count

  • 39

complete list of authors

  • Choudhury, Mahua||Qadri, Ishtiaq||Rahman, Shaikh Mizanoor||Schroeder-Gloeckler, Jill||Janssen, Rachel C||Friedman, Jacob E

publication date

  • January 2011