Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.
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
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