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oai:repisalud.isciii.es:20.500.12105/272442026-02-20T08:49:50Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Pedersen, Thomas A author Bereshchenko, Oxana author Garcia-Silva, Susana author Ermakova, Olga author Kurz, Elke author Mandrup, Susanne author Porse, Bo T author Nerlov, Claus author 2007-02-21 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. EMBO J . 2007 Feb 21;26(4):1081-93 EMBO J https://pmc.ncbi.nlm.nih.gov/articles/PMC1852842/ 17290224 https://hdl.handle.net/20.500.12105/27244 C/EBP transcription metabolism lipogenesis gluconeogenesis Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.