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The C/EBPalpha transcription factor regulates hepatic nitrogen, glucose, lipid and iron metabolism. However, how it is able to independently control these processes is not known. Here, we use mouse knock-in mutagenesis to identify C/EBPalpha domains that specifically regulate hepatic gluconeogenesis and lipogenesis. In vivo deletion of a proline-histidine rich domain (PHR), dephosphorylated at S193 by insulin signaling, dysregulated genes involved in the generation of acetyl-CoA and NADPH for triglyceride synthesis and led to increased hepatic lipogenesis. These promoters bound SREBP-1 as well as C/EBPalpha, and the PHR was required for C/EBPalpha-SREBP transcriptional synergy. In contrast, the highly conserved C/EBPalpha CR4 domain was found to undergo liver-specific dephosphorylation of residues T222 and T226 upon fasting, and alanine mutation of these residues upregulated the hepatic expression of the gluconeogenic G6Pase and PEPCK mRNAs, but not PGC-1alpha, leading to glucose intolerance. Our results show that pathway-specific metabolic regulation can be achieved through a single transcription factor containing context-sensitive regulatory domains, and indicate C/EBPalpha phosphorylation as a PGC-1alpha-independent mechanism for regulating hepatic gluconeogenesis.

Original publication

DOI

10.1038/sj.emboj.7601563

Type

Journal article

Journal

EMBO J

Publication Date

21/02/2007

Volume

26

Pages

1081 - 1093

Keywords

Amino Acid Sequence, Animals, Blotting, Western, CCAAT-Enhancer-Binding Protein-alpha, Chromatin Immunoprecipitation, DNA Primers, Gene Expression Regulation, Gluconeogenesis, Hepatocytes, Lipogenesis, Mice, Molecular Sequence Data, Mutagenesis, Phosphorylation, Polymerase Chain Reaction, Protein Structure, Tertiary, Sequence Alignment, Sterol Regulatory Element Binding Protein 1