Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice.
Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice.
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DOI：
10.3390/nu13051686
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发表时间：
2021-05-15
期刊：
影响因子：
5.9
通讯作者：
Collins JF
中科院分区：
文献类型：
--
作者：
Wang X;Zhang M;Woloshun RR;Yu Y;Lee JK;Flores SRL;Merlin D;Collins JF
肠道铁运输需要一个铁进口商（Dmt1）和一个铁出口商（Fpn1）。激素hepcidin通过调节十二指肠肠细胞基底外侧表面的Fpn1蛋白水平来调节铁吸收。在遗传性铁负荷疾病遗传性血色素沉着症（HH）中，hepcidin的产生较低，Fpn1蛋白的表达升高。高fpn1介导的铁输出耗尽细胞内铁，导致dmt1介导的铁输入矛盾地增加。这两种转运蛋白的活性增加导致铁吸收过多，从而启动体内铁负荷。因此，从逻辑上讲，肠道Dmt1或Fpn1的沉默可能是HH的有效治疗干预。先前已经确定Dmt1敲除可以阻止断奶Hamp（编码hepcidin） KO小鼠（建模型2B HH）的铁负荷。在这里，我们验证了Dmt1沉默结合饮食铁限制（可能推荐HH患者）将减轻铁负荷的假设。因此，成年Hamp KO小鼠被转换为低铁（LFe）饮食，并通过（无毒的）叶酸偶联，姜纳米颗粒衍生的脂质载体（FA-GDLVs）通过口服，每天灌胃递送阴性对照（NC）或Dmt1 siRNA，持续21天。低铁饮食减少了机体铁负荷，而实验性干预则加剧了铁的流失。例如，Dmt1 siRNA处理抑制了十二指肠Dmt1 mRNA表达（约50%），降低了血清和肝脏非血红素铁水平（分别约60%和85%）。有趣的是，一些铁相关参数同样被携带siRNA的fa - gdlv抑制，包括59Fe（作为FeCl3）的吸收（降低约20%），胰腺非血红素铁（降低约65%）和血清铁蛋白（降低40-50%）。因此，生姜可能含有影响铁稳态的生物活性脂质。综上所述，FA-GDLV和Dmt1 siRNA联合治疗，加上饮食铁限制，减轻了小鼠HH模型中预先存在的铁过载。
Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.
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30.8
作者：
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