Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis.
Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis.
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DOI：
10.1016/j.jbc.2021.101156
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Nemeth E
中科院分区：
文献类型：
--
作者：
Fisher AL;Srole DN;Palaskas NJ;Meriwether D;Reddy ST;Ganz T;Nemeth E
在血浆中，铁通常与转铁蛋白结合，转铁蛋白是血液中负责将铁结合和运输到全身的主要蛋白质。然而，在铁超载的条件下，当铁结合能力的转铁蛋白被超过，非转铁蛋白结合铁（NTBI）出现在血浆中。NTBI通过NTBI转运蛋白被肝细胞和其他实质细胞摄取，并可通过促进活性氧的产生引起细胞损伤。然而，NTBI如何影响内皮细胞，暴露于循环NTBI的最接近的细胞类型，尚未探索。我们通过用NTBI（柠檬酸铁铵[FAC]）处理原代人脐静脉内皮细胞（HUVEC），在体外模拟了全身性铁过载对内皮细胞的影响。我们通过RNA-Seq表明，铁负荷通过诱导固醇调节元件结合蛋白2介导的胆固醇生物合成来改变HUVEC中的脂质稳态。我们还确定FAC增加HUVECs对肿瘤坏死因子-α（TNFα）诱导的凋亡的敏感性。此外，我们发现胆固醇的生物合成有助于铁增强的细胞凋亡。用胆固醇螯合剂羟丙基-β-环糊精处理HUVECs表明，即使在FAC存在的情况下，胆固醇的消耗也足以拯救HUVECs免于TNFα诱导的凋亡。最后，我们发现FAC或胆固醇处理通过诱导TNFR 1的新型蛋白水解加工为定位于脂筏的短亚型来调节TNFα途径。我们的研究提出了一种可能性，即铁介导的毒性在人类铁超载疾病至少部分依赖于胆固醇代谢的改变，在内皮细胞，增加其对细胞凋亡的敏感性。
In plasma, iron is normally bound to transferrin, the principal protein in blood responsible for binding and transporting iron throughout the body. However, in conditions of iron overload when the iron-binding capacity of transferrin is exceeded, non–transferrin-bound iron (NTBI) appears in plasma. NTBI is taken up by hepatocytes and other parenchymal cells via NTBI transporters and can cause cellular damage by promoting the generation of reactive oxygen species. However, how NTBI affects endothelial cells, the most proximal cell type exposed to circulating NTBI, has not been explored. We modeled in vitro the effects of systemic iron overload on endothelial cells by treating primary human umbilical vein endothelial cells (HUVECs) with NTBI (ferric ammonium citrate [FAC]). We showed by RNA-Seq that iron loading alters lipid homeostasis in HUVECs by inducing sterol regulatory element-binding protein 2–mediated cholesterol biosynthesis. We also determined that FAC increased the susceptibility of HUVECs to apoptosis induced by tumor necrosis factor-α (TNFα). Moreover, we showed that cholesterol biosynthesis contributes to iron-potentiated apoptosis. Treating HUVECs with a cholesterol chelator hydroxypropyl-β-cyclodextrin demonstrated that depletion of cholesterol was sufficient to rescue HUVECs from TNFα-induced apoptosis, even in the presence of FAC. Finally, we showed that FAC or cholesterol treatment modulated the TNFα pathway by inducing novel proteolytic processing of TNFR1 to a short isoform that localizes to lipid rafts. Our study raises the possibility that iron-mediated toxicity in human iron overload disorders is at least in part dependent on alterations in cholesterol metabolism in endothelial cells, increasing their susceptibility to apoptosis.
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影响因子：
30.3
作者：
Arezes J;Jung G;Gabayan V;Valore E;Ruchala P;Gulig PA;Ganz T;Nemeth E;Bulut Y
通讯作者：
Bulut Y
影响因子：
9.8
作者：
Fields, M;Lewis, CG
通讯作者：
Lewis, CG
DOI：
10.1016/s0735-1097(02)02611-6
发表时间：
2002-12-18
影响因子：
24
作者：
Gaenzer, H;Marschang, P;Weiss, G
通讯作者：
Weiss, G
影响因子：
2.1
作者：
Ganz, Tomas
通讯作者：
Ganz, Tomas
影响因子：
3
作者：
Evans, Robert W.;Rafique, Roozina;Hider, Robert C.
通讯作者：
Hider, Robert C.