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J. Biol. Chem., Vol. 281, Issue 37, 27167-27177, September 15, 2006

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Inhibition of Gluconeogenesis through Transcriptional Activation of EGR1 and DUSP4 by AMP-activated Kinase^*

Stephen P. Berasi, Christine Huard, Dongmei Li, Heather H. Shih, Ying Sun, Wenyan Zhong, Janet E. Paulsen, Eugene L. Brown, Ruth E. Gimeno, and Robert V. Martinez¹

From the Departments of Biological Technologies and Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, Massachusetts 02140

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 (Glc-6-P) 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, small interfering RNA 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 the inhibition of hepatic gluconeogenesis by AMPK may, in part, be mediated by an immediate early gene response involving EGR1 and its target, DUSP4.

Received for publication, March 15, 2006 , and in revised form, July 5, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biological Technologies, Wyeth Research, 87 Cambridgepark Dr., Cambridge MA 02140. Tel.: 617-665-7008; E-mail: rxmartinez{at}wyeth.com.

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