Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

Louise E. Glover*, Brittelle E. Bowers, Bejan Saeedi, Stefan F. Ehrentraut, Eric L. Campbell, Amanda J. Bayless, Evgenia Dobrinskikh, Agnieszka A. Kendrick, Caleb J. Kelly, Adrianne Burgess, Lauren Miller, Douglas J. Kominsky, Paul Jedlicka, Sean P. Colgan

*Corresponding author for this work

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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-1a and HIF-2a 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.

Original languageEnglish
Pages (from-to)19820-19825
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number49
DOIs
Publication statusPublished - 03 Dec 2013
Externally publishedYes

Keywords

  • Actomyosin
  • Energy metabolism
  • Epithelial junctions
  • IBD

ASJC Scopus subject areas

  • General

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  • Cite this

    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. (2013). Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proceedings of the National Academy of Sciences of the United States of America, 110(49), 19820-19825. https://doi.org/10.1073/pnas.1302840110