TY - JOUR
T1 - Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.
AU - Pedersen, Thomas A
AU - Bereshchenko, Oxana
AU - Garcia-Silva, Susana
AU - Ermakova, Olga
AU - Kurz, Elke
AU - Mandrup, Susanne
AU - Porse, Bo T
AU - Nerlov, Claus
N1 - 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
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
U2 - 10.1038/sj.emboj.7601563
DO - 10.1038/sj.emboj.7601563
M3 - Journal article
C2 - 17290224
SN - 0261-4189
VL - 26
SP - 1081
EP - 1093
JO - E M B O Journal
JF - E M B O Journal
IS - 4
ER -