Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.
Research output: Contribution to journal › Journal article › Research › peer-review
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 language | English |
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Journal | EMBO Journal |
Volume | 26 |
Issue number | 4 |
Pages (from-to) | 1081-93 |
Number of pages | 12 |
ISSN | 0261-4189 |
DOIs | |
Publication status | Published - 2007 |
Bibliographical note
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
ID: 5140537