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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Fasting
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Enzymologic
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Glucose / metabolism*
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Glucose-6-Phosphatase / genetics*
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Glucose-6-Phosphatase / metabolism
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Glycogen Storage Disease Type I / genetics*
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Glycogen Storage Disease Type I / metabolism
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Hepatocytes / metabolism
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Kidney / metabolism
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Liver / metabolism*
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Liver Glycogen / metabolism
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Male
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Mice
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Mice, Knockout
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Nuclear Receptor Coactivator 2 / genetics
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Nuclear Receptor Coactivator 2 / metabolism*
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RNA Interference
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Receptors, Retinoic Acid / metabolism
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Response Elements
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Retinoic Acid Receptor alpha
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Transcription, Genetic
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Triglycerides / metabolism
Substances
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Liver Glycogen
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Ncoa2 protein, mouse
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Nuclear Receptor Coactivator 2
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Rara protein, mouse
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Triglycerides
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Glucose-6-Phosphatase
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Glucose