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

Journal article

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.

Authors: Pedersen, T; Bereshchenko, O; Garcia-Silva, S; Ermakova, O; Kurz, E

• Journal: EMBO journal
• Volume: 26
• Issue: 4
• Pages: 1081-1093
• Publication date: 2007-02-01
• DOI: 10.1038/sj.emboj.7601563
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: DNA Primers; Amino Acid Sequence; Hepatocytes; Chromatin Immunoprecipitation; Molecular Sequence Data; Polymerase Chain Reaction; Phosphorylation; Mutagenesis; Animals; CCAAT-Enhancer-Binding Protein-alpha; Sterol Regulatory Element Binding Protein 1; Lipogenesis; Protein Structure, Tertiary; Gluconeogenesis; Sequence Alignment; Mice; Gene Expression Regulation; Blotting, Western