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


  • 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 RORalpha. 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.


  • Chopra, AR
  • Louet, J-F
  • Saha, P
  • An, J
  • DeMayo, F
  • Xu, J
  • York, B
  • Karpen, S
  • Finegold, M
  • Moore, D
  • Chan, L
  • Newgard, CB
  • O'Malley, BW

publication date

  • November 28, 2008

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