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Science 322 (5906): 1395-1399

Copyright © 2008 by the American Association for the Advancement of Science

Absence of the SRC-2 Coactivator Results in a Glycogenopathy Resembling Von Gierke's Disease

Atul R. Chopra,1* Jean-Francois Louet,1* Pradip Saha,1 Jie An,4 Franco DeMayo,1 Jianming Xu,1 Brian York,1 Saul Karpen,1,2 Milton Finegold,3 David Moore,1 Lawrence Chan,1 Christopher B. Newgard,4 Bert W. O'Malley1{dagger}

Abstract: Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the plasma. Mutations in G6Pase result in Von Gierke's disease (glycogen storage disease–1a), a potentially fatal genetic disorder. We have identified the transcriptional coactivator SRC-2 as a regulator of fasting hepatic glucose release, a function that SRC-2 performs by controlling the expression of hepatic G6Pase. SRC-2 modulates G6Pase expression directly by acting as a coactivator with the orphan nuclear receptor ROR{alpha}. In addition, SRC-2 ablation, in both a whole-body and liver-specific manner, resulted in a Von Gierke's disease phenotype in mice. Our results position SRC-2 as a critical regulator of mammalian glucose production.

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
2 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
3 Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
4 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC27710, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: berto{at}

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