TY - JOUR
T1 - Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis
AU - Glover, Louise E.
AU - Bowers, Brittelle E.
AU - Saeedi, Bejan
AU - Ehrentraut, Stefan F.
AU - Campbell, Eric L.
AU - Bayless, Amanda J.
AU - Dobrinskikh, Evgenia
AU - Kendrick, Agnieszka A.
AU - Kelly, Caleb J.
AU - Burgess, Adrianne
AU - Miller, Lauren
AU - Kominsky, Douglas J.
AU - Jedlicka, Paul
AU - Colgan, Sean P.
PY - 2013/12/3
Y1 - 2013/12/3
N2 - 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.
AB - 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.
KW - Actomyosin
KW - Energy metabolism
KW - Epithelial junctions
KW - IBD
UR - http://www.scopus.com/inward/record.url?scp=84889673983&partnerID=8YFLogxK
U2 - 10.1073/pnas.1302840110
DO - 10.1073/pnas.1302840110
M3 - Article
C2 - 24248342
AN - SCOPUS:84889673983
VL - 110
SP - 19820
EP - 19825
JO - Proceedings of the National Academy of Sciences
JF - Proceedings of the National Academy of Sciences
SN - 0027-8424
IS - 49
ER -