ArticleThe EMBO journal2007
Distinct C/EBPalpha motifs regulate lipogenic and gluconeogenic gene expression in vivo.
Article in The EMBO journal, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 77 citations in OpenAlex.
- Trial
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- Interferon alpha-inducible protein 27 (IFI27) inhibits hepatitis B virus (HBV) transcription through downregulating cellular transcription factor C/EBPα.Journal of virology · 2025Article
- Cholesterol metabolism: molecular mechanisms, biological functions, diseases, and therapeutic targets.Molecular biomedicine · 2025Review
- A review of C/EBP α: a potential novel target for solid tumor intervention.Journal of translational medicine · 2025Review
- Conditional knockout of C/EBPβ in epidermis results in dysregulated lipid biosynthesis and a defect in skin barrier function.PloS one · 2025Article
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- Biochemical Pathways Represented by Gene Ontology Causal Activity Models Identify Distinct Phenotypes Resulting from Mutations in Pathways.bioRxiv : the preprint server for biology · 2023Article
- Anti-obesity effects of Lactiplantibacillus plantarum SKO-001 in high-fat diet-induced obese mice.European journal of nutrition · 2023Article
- GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway.Nature communications · 2022Article
- Review
- Sirtuin Oxidative Post-translational Modifications.Frontiers in physiology · 2021Review
- Integration of chronological omics data reveals mitochondrial regulatory mechanisms during the development of hepatocellular carcinoma.PloS one · 2021Article
- E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα.Oncogene · 2021Article
- Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation.International journal of molecular sciences · 2020Article
- Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH.Liver international : official journal of the International Association for the Study of the Liver · 2020Article
- Comparative Transcriptomic Analysis of Subcutaneous Adipose Tissue from Local Pig Breeds.Genes · 2020Article
- Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet.Nature communications · 2020Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.