Pedersen, Thomas ABereshchenko, OxanaGarcia-Silva, SusanaErmakova, OlgaKurz, ElkeMandrup, SusannePorse, Bo TNerlov, Claus2026-02-202026-02-202007-02-21EMBO J . 2007 Feb 21;26(4):1081-93https://hdl.handle.net/20.500.12105/27244The 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.engNAhttp://creativecommons.org/licenses/by-nc-nd/4.0/C/EBPtranscriptionmetabolismlipogenesisgluconeogenesisAttribution-NonCommercial-NoDerivatives 4.0 International172902242641081-1093EMBO Jhttps://pmc.ncbi.nlm.nih.gov/articles/PMC1852842/metadata only access