HIF1α-Dependent Induction of TFRC by a Combination of Intestinal Inflammation and Systemic Iron Deficiency in Inflammatory Bowel Disease.
HIF1α-Dependent Induction of TFRC by a Combination of Intestinal Inflammation and Systemic Iron Deficiency in Inflammatory Bowel Disease.
复制标题
DOI：
10.3389/fphys.2022.889091
复制
发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
背景和目标：缺铁（ID）是炎症性肠病（IBD）患者常见的肠外表现，通常对铁补充剂无反应。铁是羟化酶的辅因子，羟化酶抑制低氧诱导因子-1 α（HIF 1 α），HIF 1 α是一种调节铁稳态的转录因子。我们假设缺铁影响IBD时粘膜HIF 1 α活性。 研究方法：IBD患者（n = 101）根据铁状态（铁蛋白水平或转铁蛋白饱和度）和全身炎症（C反应蛋白水平）进行细分。分析了154例相应的回肠和结肠活检组织中20个HIF 1 α通路相关基因的差异表达，并与铁和炎症状态相关。在野生型和HIF 1A缺失的Caco-2细胞中分析了选定HIF 1 α途径基因的体外表达。 结果：肠黏膜HIF 1 α通路的基因表达受肠道位置和炎症状态的影响最大。特别地，编码转铁蛋白受体TFR 1的回肠粘膜TFRC表达在发炎组织中增加（p < 0.001），并且在ID中进一步增强。因此，TFRC在发炎组织中的表达与血清铁水平负相关，这在非发炎粘膜中未观察到。HIF 1 α通路激动剂DMOG增加了Caco-2细胞中TFRC的表达，这在HIF 1A-null细胞中是钝化的。 结论：我们证明炎症和解剖位置主要决定了肠粘膜中HIF 1 α通路的激活和下游TFRC的表达。IBD ID患者可通过以下方式从HIF 1 α激动剂治疗中获益：1）增加非炎症组织中TFRC介导的铁吸收; 2）减少粘膜炎症，从而改善其对口服补铁的反应性。
Background and Aims: Iron deficiency (ID) is a frequent extra-intestinal manifestation in patients with Inflammatory Bowel Disease (IBD), who often do not respond to iron supplementation. Iron is a cofactor for hydroxylases that suppress the hypoxia-inducible factor-1α (HIF1α), a transcription factor regulating iron homeostasis. We hypothesized that iron deficiency affects mucosal HIF1α activity in IBD. Methods: IBD patients (n = 101) were subdivided based on iron status (ferritin levels or transferrin saturation) and systemic inflammation (C-reactive protein levels). 154 corresponding ileal and colonic biopsies were analyzed for differential expression of 20 HIF1α pathway-associated genes and related to iron and inflammation status. In vitro expression of selected HIF1α pathway genes were analyzed in wild-type and HIF1A-null Caco-2 cells. Results: Gene expression of the mucosal HIF1α pathway was most affected by intestinal location and inflammatory status. Especially, ileal mucosal TFRC expression, encoding the transferrin receptor TFR1, was increased in inflamed tissue (p < 0.001), and further enhanced in ID. Accordingly, TFRC expression in inflamed tissue associated negatively with serum iron levels, which was not observed in the non-inflamed mucosa. The HIF1α pathway agonist DMOG increased TFRC expression in Caco-2 cells, which was blunted in HIF1A-null cells. Conclusion: We demonstrate that inflammation and anatomical location primarily determine HIF1α pathway activation and downstream TFRC expression in the intestinal mucosa. IBD patients with ID may benefit from treatment with HIF1α-agonists by 1) increasing TFRC-mediated iron absorption in non-inflamed tissue and 2) decreasing mucosal inflammation, thereby improving their responsiveness to oral iron supplementation.
登录
查看更多内容
影响因子：
29.4
作者：
Cummins, Eoin P.;Seeballuck, Fergal;Taylor, Cormac T.
通讯作者：
Taylor, Cormac T.
铁调节蛋白 1 抑制缺氧诱导的铁摄取蛋白表达并降低 HepG2 细胞中的铁水平
影响因子：
4
作者：
Cheng, Chun-Ming;Wang, Dan;Zhu, Li
通讯作者：
Zhu, Li
影响因子：
8
作者：
Dignass, Axel U.;Gasche, Christoph;Vavricka, Stephan
通讯作者：
Vavricka, Stephan
影响因子：
1.9
作者：
Gonzalez Alayon, Carlos;Pedrajas Crespo, Carolina;Garcia-Sanchez, Valle
通讯作者：
Garcia-Sanchez, Valle
影响因子：
4.9
作者：
Herrera-deGuise, Claudia;Casellas, Francesc;Borruel, Natalia
通讯作者：
Borruel, Natalia