C/EBPβ is AMP kinase sensitive and up-regulates PEPCK in response to ER stress in hepatoma cells.
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/EBPβ) 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/EBPβ is recruited to the PEPCK promoter during ER stress and is reversed by pre-treatment with a JNK inhibitor that relieves ER stress. C/EBPβ but not pCREB was suppressed by the AMPK-activator AICAR or constitutively active AMPK, while dominant negative AMPK increased C/EBPβ expression. These data suggest that ER stress triggers suppression of AMPK while increasing C/EBPβ and pCREB expression which activates PEPCK gene transcription. Understanding how ER stress suppresses AMPK activation and increases C/EBPβ expression could lead to a potentially novel pathway for treatment of diabetes.
Choudhury
Mahua
M
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
Qadri
Ishtiaq
I
Rahman
Shaikh Mizanoor
SM
Schroeder-Gloeckler
Jill
J
Janssen
Rachel C
RC
Friedman
Jacob E
JE
D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D020218:Response Elements / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D019284:Thapsigargin; D000263:Adenylate Kinase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
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