Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland;
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland; Department of Gastroenterology and Hepatology, University Clinic Würzburg, Würzburg, Germany;
Am J Physiol Gastrointest Liver Physiol. 2014 Oct 1;307(7):G673-88. doi: 10.1152/ajpgi.00353.2013. Epub 2014 Jun 26.
Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2 or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals (n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans.
溶质载体 (SLC) 转运蛋白介导肠道中生物活性化合物的摄取。低氧（缺氧）是影响肠道内稳态的重要因素。本研究旨在探讨缺氧对人肠 SLC 表达和功能的病理生理影响。在体外（0.2；1% O2 或 CoCl2）诱导人肠上皮细胞 (IEC) 缺氧。对于人体的体内研究，从急性暴露于海拔 4554 米的个体中获得十二指肠活检和血清样本（n = 16）。通过定量 PCR、Western blot 或免疫荧光分析相关靶标的表达。通过 ELISA 和 LC/MS-MS 分别测定血清中炎症介质和核苷的水平。在暴露于高海拔的志愿者的十二指肠中，我们观察到顶端钠依赖性胆汁酸转运蛋白 (ASBT)、协同核苷转运蛋白 1/2 (CNT1/2)、有机阴离子转运多肽 2B1 (OATP2B1)、有机阳离子转运蛋白 2 (OCTN2)、肽转运蛋白 1 (PEPT1)、血清素转运体 (SERT) 的 mRNA 水平降低，而 IFN-γ、IL-6 和 IL-17A 的水平升高。血清中 IL-10、IFN-γ、基质金属蛋白酶-2 (MMP-2) 和血清素水平升高，而尿苷水平在缺氧暴露时降低。缺氧 IEC 显示体外平衡核苷转运蛋白 2 (ENT2)、OCTN2 和 SERT mRNA 水平降低，在蛋白水平得到证实，并伴有 ERK1/2 激活、缺氧诱导因子 (HIF) 蛋白增加和 IL-8 mRNA 产生。缺氧时与 IFN-γ 和 IL-6 共刺激进一步降低了 SERT、ENT2 和 CNT2 的表达。氧供应减少会影响十二指肠 SLC 的表达模式，同时血清中促炎细胞因子和生物活性化合物的水平也会发生变化，表明在人体系统暴露于缺氧时，肠道转运受到影响。
