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

Abstract

The C/EBPα 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/EBPα 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/EBPα, and the PHR was required for C/EBPα‐SREBP transcriptional synergy. In contrast, the highly conserved C/EBPα 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‐1α, 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/EBPα phosphorylation as a PGC‐1α‐independent mechanism for regulating hepatic gluconeogenesis.