title: Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.
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 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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Atul R
authors.initials: AR
authors.lastname: Chopra
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Louet
authors.forename: Pradip
authors.initials: P
authors.lastname: Saha
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.forename: Franco
authors.initials: F
authors.lastname: Demayo
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.forename: Saul
authors.initials: S
authors.lastname: Karpen
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005215:Fasting; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008112:Liver Glycogen; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014280:Triglycerides; D005952:Glucose-6-Phosphatase; D005947:Glucose