Characterization of ferroptosis in murine models of hemochromatosis.
Characterization of ferroptosis in murine models of hemochromatosis.
复制标题
血色素沉着症小鼠模型中铁死亡的特征
DOI：
10.1002/hep.29117
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Wang H;An P;Xie E;Wu Q;Fang X;Gao H;Zhang Z;Li Y;Wang X;Zhang J;Li G;Yang L;Liu W;Min J;Wang F
铁下垂是最近发现的一种铁依赖的非凋亡性细胞死亡形式，与脑、肾脏和心脏的病理有关。然而，铁和铁代谢在铁性下垂中的生物学作用仍然知之甚少。在这里，我们研究了铁和铁代谢在铁性下垂发病机制中的功能作用。我们发现柠檬酸铁能有效地诱导小鼠原代肝细胞和骨髓来源的巨噬细胞发生铁下垂。接下来，我们对高铁饮食的小鼠和铁负荷过高的遗传性血色素沉着症的小鼠进行了铁性下垂的筛查。我们发现，铁下垂发生在喂食高铁饲料的小鼠和两个发生严重铁超载的基因敲除小鼠品系(Hjv-/-和Smad4Alb/Alb小鼠)中，但在第三个品系只出现轻微铁超载的小鼠(HFe-/-小鼠)中没有。此外，我们还发现铁超负荷引起的肝损伤可以被铁下垂抑制剂铁蛋白-1拯救。为了确定铁诱导的铁下垂相关基因，我们对铁处理后的骨髓来源的巨噬细胞进行了基因芯片分析。有趣的是，溶质载体家族7，11成员(Slc7a11)，一个已知的铁下垂相关基因，在铁处理的细胞中比未处理的细胞显著上调。然而，从基因上删除SLC7a11的表达并不足以诱导小鼠的铁下垂。接下来，我们研究了铁处理过的肝细胞和从高铁饮食中分离出来的SLC7a11-/-小鼠的骨髓巨噬细胞。结论：我们发现铁处理诱导了SLc7a11-/-细胞的铁性下垂，表明缺失Slc7a11促进了高铁条件下铁性下垂的发生；这些结果提供了令人信服的证据，表明铁在触发SLc7a11介导的铁性下垂中起关键作用，并提示铁性下垂可能是治疗血色病相关组织损伤的一个有前景的靶点。(《肝病》2017；66：449-465)。
Ferroptosis is a recently identified iron‐dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow–derived macrophages. Next, we screened for ferroptosis in mice fed a high‐iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high‐iron diet and in two knockout mouse lines that develop severe iron overload (Hjv–/– and Smad4Alb/Alb mice) but not in a third line that develops only mild iron overload (Hfe –/– mice). Moreover, we found that iron overload–induced liver damage was rescued by the ferroptosis inhibitor ferrostatin‐1. To identify the genes involved in iron‐induced ferroptosis, we performed microarray analyses of iron‐treated bone marrow–derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis‐related gene, was significantly up‐regulated in iron‐treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron‐treated hepatocytes and bone marrow–derived macrophages isolated from Slc7a11–/– mice fed a high‐iron diet. Conclusion: We found that iron treatment induced ferroptosis in Slc7a11–/– cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high‐iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11‐mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis‐related tissue damage. (Hepatology 2017;66:449–465).
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
DOI：
10.1073/pnas.1415518111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Linkermann, Andreas;Skouta, Rachid;Krautwald, Stefan
通讯作者：
Krautwald, Stefan