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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 49; pp. 19820 - 19825
• Main Authors: Glover, Louise E., Bowers, Brittelle E., Saeedi, Bejan, Ehrentraut, Stefan F., Campbell, Eric L., Bayless, Amanda J., Dobrinskikh, Evgenia, Kendrick, Agnieszka A., Kelly, Caleb J., Burgess, Adrianne, Miller, Lauren, Kominsky, Douglas J., Jedlicka, Paul, Colgan, Sean P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.12.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: adenosine triphosphate; adherens junctions; Analysis of Variance; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Bioenergetics; Biological Sciences; Blotting, Western; Cadherins; Cell Hypoxia - physiology; Chromatography, High Pressure Liquid; Colitis; Colitis - metabolism; Creatine; Creatine - metabolism; Creatine Kinase - metabolism; Crohn disease; dietary supplements; disease severity; DNA Primers - genetics; energy metabolism; Enzymes; Epithelial cells; Flow Cytometry; Fluorescent Antibody Technique; gastrointestinal system; Gastrointestinal tract; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Enzymologic - physiology; Gene Knockdown Techniques; genes; homeostasis; Humans; Hypoxia; hypoxia-inducible factor 1; Immunoprecipitation; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Kinases; Metabolic diseases; Metabolism; Mice; mucosa; oxygen; patients; phosphotransferases (kinases); Polymerase Chain Reaction; Signal Transduction - physiology; transcriptional activation; IBD; epithelial junctions; actomyosin; energy metabolism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1302840110

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.