Liver sinusoidal endothelial cells induce BMP6 expression in response to non-transferrin-bound iron
Liver sinusoidal endothelial cells induce BMP6 expression in response to non-transferrin-bound iron
复制标题
DOI：
10.1182/blood.2022016987
复制
发表时间：
2023-01-19
期刊：
影响因子：
20.3
通讯作者：
Pantopoulos, Kostas
中科院分区：
文献类型：
--
作者：
Charlebois, Edouard;Fillebeen, Carine;Pantopoulos, Kostas
对系统性铁过载的稳态适应涉及肝窦内皮细胞（LSEC）中骨形态发生蛋白6（BMP 6）的转录诱导。然后分泌BMP 6以激活邻近肝细胞中铁激素铁调素（HAMP）的信号传导。为了探索LSECs的铁传感机制，我们产生了转铁蛋白受体1（Tfr 1）内皮细胞特异性消融Tfrc（Tek-Cre）小鼠。我们还使用对照Tfrc（fl/fl）小鼠，使用单细胞转录组学来表征对铁的LSEC特异性分子反应。与Tfrc（fl/fl）对照相比，Tfrc（Tek-Cre）动物倾向于具有适度增加的肝脏铁含量（LIC），但表达生理性Bmp 6和Hamp信使RNA（mRNA）。尽管暂时不能上调Bmp 6，但它们最终对Bmp 6和Hamp诱导的铁挑战做出反应，但偶尔会达到相对于LIC略低的水平。高膳食铁摄入量引发的血清非转铁蛋白结合铁（NTBI），这与肝脏Bmp 6和Hamp mRNA水平显着相关的积累，并引起更深刻的改变，在LSEC转录比全息转铁蛋白注射。这最终导致Bmp 6和其他核因子红细胞2相关因子2（Nrf 2）靶基因，以及参与核糖体生物发生和蛋白质合成的Myc靶基因的稳健诱导。LSEC和中间带肝细胞是对铁挑战最敏感的肝细胞，并分别表现出Bmp 6和Hamp mRNA的最高表达。我们的数据表明，在全身性铁超载，LSEC内化NTBI，促进氧化应激，从而通过Nrf 2转录诱导Bmp 6。Tfr 1似乎有助于LSECs的铁传感，主要是在低铁条件下。
Homeostatic adaptation to systemic iron overload involves transcriptional induction of bone morphogenetic protein 6 (BMP6) in liver sinusoidal endothelial cells (LSECs). BMP6 is then secreted to activate signaling of the iron hormone hepcidin (HAMP) in neighboring hepatocytes. To explore the mechanism of iron sensing by LSECs, we generated Tfrc(Tek-Cre) mice with endothelial cell-specific ablation of transferrin receptor 1 (Tfr1). We also used control Tfrc(fl/fl) mice to characterize the LSEC-specific molecular responses to iron using single-cell transcriptomics. Tfrc(Tek-Cre) animals tended to have modestly increased liver iron content (LIC) compared with Tfrc(fl/fl) controls but expressed physiological Bmp6 and Hamp messenger RNA (mRNA). Despite a transient inability to upregulate Bmp6, they eventually respond to iron challenges with Bmp6 and Hamp induction, yet occasionally to levels slightly lower relative to LIC. High dietary iron intake triggered the accumulation of serum nontransferrin bound iron (NTBI), which significantly correlated with liver Bmp6 and Hamp mRNA levels and elicited more profound alterations in the LSEC transcriptome than holo-transferrin injection. This culminated in the robust induction of Bmp6 and other nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, as well as Myc target genes involved in ribosomal biogenesis and protein synthesis. LSECs and midzonal hepatocytes were the most responsive liver cells to iron challenges and exhibited the highest expression of Bmp6 and Hamp mRNAs, respectively. Our data suggest that during systemic iron overload, LSECs internalize NTBI, which promotes oxidative stress and thereby transcriptionally induces Bmp6 via Nrf2. Tfr1 appears to contribute to iron sensing by LSECs, mostly under low iron conditions.