Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin.
Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin.
复制标题
DOI：
10.1016/j.kint.2021.10.036
复制
发表时间：
2022-04
影响因子：
19.6
通讯作者：
Ganz T
中科院分区：
文献类型：
--
作者：
Hanudel MR;Czaya B;Wong S;Rappaport M;Namjoshi S;Chua K;Jung G;Gabayan V;Qiao B;Nemeth E;Ganz T
柠檬酸铁被批准为非透析慢性肾脏疾病和缺铁性贫血患者的铁替代产品。柠檬酸铁转运的铁在肠道中被吸收，但涉及的具体机制尚未被评估，包括传统的跨细胞铁蛋白介导的吸收和/或柠檬酸介导的细胞旁吸收的可能性。在这里，我们首先证明了柠檬酸铁在高海普西丁模型中的有效性，包括Tmprss 6基因敲除小鼠(特征是铁耐受性缺铁性贫血)，并伴有和不伴有腺嘌呤饮食诱导的慢性肾脏疾病。接下来，为了评估肠内柠檬酸铁吸收是否依赖于铁蛋白，我们在他莫昔芬诱导的肠道细胞特异性铁蛋白基因敲除小鼠模型(Villin-CRE-ERT2，Fpnflx/FLOX)中评估了柠檬酸铁的作用。在该模型中，铁蛋白缺失是有效的，因为他莫昔芬诱导十二指肠铁蛋白表达下降4000倍，在十二指肠肠上皮细胞的Western印迹中检测不到铁蛋白，导致严重的缺铁性贫血表型。在铁转运蛋白缺乏的小鼠中，三周的1%柠檬酸铁饮食补充剂，这种剂量可以防止对照组小鼠缺铁，并没有改善铁状况或挽救缺铁性贫血的表型。我们使用腺嘌呤肾病模型，在尿毒症患者中重复了条件铁蛋白基因敲除实验，在该模型中，再次服用1%柠檬酸铁饮食三周未能改善铁状况或挽救缺铁性贫血表型。因此，我们的数据表明，肠内柠檬酸铁的吸收依赖于传统的肠细胞铁转运，在这些模型中，不会发生显著的细胞旁吸收。
Ferric citrate is approved as an iron replacement product in patients with non-dialysis chronic kidney disease and iron deficiency anemia. Ferric citrate-delivered iron is enterally absorbed, but the specific mechanisms involved have not been evaluated, including the possibilities of conventional, transcellular ferroportin-mediated absorption and/or citrate-mediated paracellular absorption. Here, we first demonstrate the efficacy of ferric citrate in high hepcidin models, including Tmprss6 knockout mice (characterized by iron-refractory iron deficiency anemia) with and without adenine diet–induced chronic kidney disease. Next, to assess whether or not enteral ferric citrate absorption is dependent on ferroportin, we evaluated the effects of ferric citrate in a tamoxifen-inducible, enterocyte-specific ferroportin knockout murine model (Villin-Cre-ERT2, Fpnflox/flox). In this model, ferroportin deletion was efficient, as tamoxifen injection induced a 4000-fold decrease in duodenum ferroportin mRNA expression, with undetectable ferroportin protein on Western blot of duodenal enterocytes, resulting in a severe iron deficiency anemia phenotype. In ferroportin-deficient mice, three weeks of 1% ferric citrate dietary supplementation, a dose that prevented iron deficiency in control mice, did not improve iron status or rescue the iron deficiency anemia phenotype. We repeated the conditional ferroportin knockout experiment in the setting of uremia, using an adenine nephropathy model, where three weeks of 1% ferric citrate dietary supplementation again failed to improve iron status or rescue the iron deficiency anemia phenotype. Thus, our data suggest that enteral ferric citrate absorption is dependent on conventional enterocyte iron transport by ferroportin and that, in these models, significant paracellular absorption does not occur.
登录
查看更多内容
影响因子：
5.6
作者：
Wilkinson N;Pantopoulos K
通讯作者：
Pantopoulos K
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
2.7
作者：
Troutt, Jason S.;Butterfield, Anthony M.;Konrad, Robert J.
通讯作者：
Konrad, Robert J.
DOI：
10.1152/ajprenal.00676.2013
发表时间：
2014-12-01
影响因子：
4.2
作者：
Diwan, Vishal;Small, David;Brown, Lindsay
通讯作者：
Brown, Lindsay
影响因子：
13.6
作者：
Lewis, Julia B.;Sika, Mohammed;Dwyer, Jamie P.
通讯作者：
Dwyer, Jamie P.