| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print July 18, 2006
Biological Technologies, Wyeth, Cambridge, MA 02140
Corresponding Author: rxmartinez{at}wyeth.com
Increased hepatic gluconeogenesis is an important contributor to the fasting hyperglycemia found in Type 2 diabetic patients. Low energy states activate the intracellular energy sensor AMP Activated Kinase (AMPK). AMPK activation by the AMP mimetic AICAR (5-aminoimidazole-4- carboxamide riboside) has been shown to inhibit hepatic gluconeogenesis. We used transcriptional profiling to search for AICAR-regulated genes in hepatocyte cell lines. We report that a dual specificity phosphatase, DUSP4, is induced by AMPK in AML12, H4IIE, and Fao cells at both mRNA and protein levels. AMPK also induces the immediate early transcription factor EGR1 (Early Growth Response 1), a known transcriptional activator of DUSP4, and it directly binds the DUSP4 promoter at its known binding site. Both reporter gene assays and real time PCR demonstrate that exogenous DUSP4 inhibits the promoter activity and expression of both glucose-6- phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) to an extent similar to both AICAR and constitutively active AMPK. Conversely, depletion of EGR1 or DUSP4 using siRNA not only partially abrogates the inhibition of PEPCK expression by AICAR, but also importantly affects glucose production by Fao cells. In Fao cells, siRNA targeted EGR1 also depletes DUSP4 expression following treatment with AICAR, further supporting a direct link between EGR1 and DUSP4 activation. Expression of a constitutively active form of p38, a known effector of cAMP mediated gluconeogenesis, rescues the DUSP4 mediated repression of PEPCK. These results suggest that AMPK’s inhibition of hepatic gluconeogenesis may, in part, be mediated by an immediate early gene response involving EGR1 and its target, DUSP4.
J. Biol. Chem, 10.1074/jbc.M602416200
Submitted on March 15, 2006
Accepted on July 18, 2006
Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP 4 by AMPK
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Bell, H. Wang, H. Chen, J. C. McLenithan, D.-W. Gong, R.-Z. Yang, D. Yu, S. K. Fried, M. J. Quon, C. Londos, et al. Consequences of Lipid Droplet Coat Protein Downregulation in Liver Cells: Abnormal Lipid Droplet Metabolism and Induction of Insulin Resistance Diabetes, August 1, 2008; 57(8): 2037 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Y. Liu, Q. F. Collins, F. Moukdar, D. Zhuo, J. Han, T. Hong, S. Collins, and W. Cao Suppression of Hepatic Glucose Production by Human Neutrophil {alpha}-Defensins through a Signaling Pathway Distinct from Insulin J. Biol. Chem., May 2, 2008; 283(18): 12056 - 12063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Krawiec, G. J. Nystrom, R. A. Frost, L. S. Jefferson, and C. H. Lang AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1555 - E1567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arad, C. E. Seidman, and J.G. Seidman AMP-Activated Protein Kinase in the Heart: Role During Health and Disease Circ. Res., March 2, 2007; 100(4): 474 - 488. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
