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Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis
Open accessAbstract
Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine-creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2-dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.
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“a 50% down-regulation of creatine kinase Ckb and Ckm genes suggests a reduced efficacy of phosphocreatine metabolic shuttle turnover, which is critically important for the maintenance of energy supply to TJs (Glover et al., 2013).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Glover et al., 2013
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Metadata
- Authors
- Glover, L. E., Bowers, B. E., Saeedi, B., Ehrentraut, S. F., Campbell, E. L., Bayless, A. J., Dobrinskikh, E., Kendrick, A. A., Kelly, C. J., Burgess, A., Miller, L., Kominsky, D. J., Jedlicka, P., & Colgan, S. P.
- Affiliations
- University of Colorado Anschutz (US)
- Mucosal Inflammation Program,
- Department of Medicine,
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-11-18
- Volume
- 110
- Issue
- 49
- Pages
- 19820-19825
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3856803
- OpenAlex
- W2066159720
- Cited by
- 155
- References
- 37
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 12 · 2023: 17 · 2022: 14 · 2021: 10 · 2020: 10 · 2019: 10 · 2018: 8 · 2017: 13 · 2016: 16 · 2015: 8 · 2014: 7
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL060569, HL-60569)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050189, DK095491, R37DK050189, R29DK050189, DK-50189, R01DK095491)
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Gastroenterology › Digestive system and related health
- Keywords
- creatine kinase, hypoxia-inducible factor, HIF-1α, HIF-2α, colitis, intestinal epithelial barrier, adherens junctions, ulcerative colitis, Crohn's disease, hypoxia, bioenergetics, mucosal inflammation
- MeSH terms
- Analysis of Variance, Chromatography, High Pressure Liquid, Colitis, Creatine, Creatine Kinase, Flow Cytometry, Fluorescent Antibody Technique, Humans, Blotting, Western, Signal Transduction, Cell Hypoxia, Gene Expression Regulation, Enzymologic, Polymerase Chain Reaction, DNA Primers, Immunoprecipitation, Aryl Hydrocarbon Receptor Nuclear Translocator, Gene Knockdown Techniques
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