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.
Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19820-5. doi: 10.1073/pnas.1302840110. Epub 2013 Nov 18.
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.
下消化道的黏膜表面经常受到氧气张力的明显波动的影响，特别是在炎症期间。缺氧适应反应主要由缺氧诱导转录因子（HIFs）协调。由于 HIF-1α 和 HIF-2α 在构成腔和下面的免疫环境之间屏障的黏膜上皮中共同表达，我们试图确定 HIF-1 和 HIF-2 转录激活途径对肠上皮细胞稳态的不同贡献。本研究确定肌酸激酶（CKs），即通过磷酸肌酸-肌酸激酶（PCr/CK）系统快速产生 ATP 的关键代谢酶，作为一个独特的基因家族，由 HIF 协调调节。细胞质 CKs 在体外以 HIF-2 依赖的方式表达，并定位于肠上皮细胞顶端的黏着连接，在那里它们对于连接组装和上皮完整性至关重要。膳食肌酸的补充显著改善了结肠炎模型中的疾病严重程度和炎症反应。此外，PCr/CK 代谢穿梭的酶在溃疡性结肠炎和克罗恩病患者的一部分中表现出黏膜表达失调。这些发现确立了 HIF 调节的 CK 在上皮稳态中的作用，并揭示了细胞生物能学和黏膜屏障之间的基本联系。
