title: Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis.
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-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.
authors.affiliation: Mucosal Inflammation Program, Department of Medicine, Department of Anesthesiology and Perioperative Medicine, and Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Bowers
authors.forename: Bejan
authors.initials: B
authors.lastname: Saeedi
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Ehrentraut
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bayless
authors.forename: Evgenia
authors.initials: E
authors.lastname: Dobrinskikh
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kendrick
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Kelly
authors.forename: Adrianne
authors.initials: A
authors.lastname: Burgess
authors.forename: Lauren
authors.initials: L
authors.lastname: Miller
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000704:Analysis of Variance; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000378:metabolism*; D003401:Creatine / Q000378:metabolism*; D003402:Creatine Kinase / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003402:Creatine Kinase; D003401:Creatine
keywords: IBD; actomyosin; energy metabolism; epithelial junctions