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  • The EMBO Journal (2007) 26, 1081 - 1093
  • doi:10.1038/sj.emboj.7601563

Published online: 8 February 2007

Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo

Thomas Å Pedersen1,2, Oxana Bereshchenko1, Susana Garcia-Silva1, Olga Ermakova1, Elke Kurz1, Susanne Mandrup2, Bo T Porse3 and Claus Nerlov1

  1. EMBL Mouse Biology Unit, Monterotondo, Italy
  2. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
  3. Laboratory of Gene Therapy Research, Copenhagen University Hospital, Copenhagen Ø, Denmark

Correspondence to:

Claus Nerlov, Mouse Biology Unit, EMBL, via Ramarini 32, 00016 Monterotondo, Italy. Tel.: +39 06 9009 1218; Fax: +39 06 9009 1272; E-mail: nerlov@embl-monterotondo.it

Received 23 March 2006; Accepted 20 December 2006

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.

  • Keywords:

    • C/EBP,
    • gluconeogenesis,
    • lipogenesis,
    • metabolism,
    • transcription