LncRNA调控TFR2表达在慢性应激诱发猪肝脏铁过载中的作用及机制研究

With the development of intensive production in pig industry, various kinds of stress factors become more frequent and more severe. The pigs are suffered from the chronic stress. Chronic stress reduces the pig's performance, causes hepatic iron overload, induces oxidative stress, and then affects the health of the pigs. Our previous study showed that chronic stress resulted in hepatic iron overload, which was closely related to liver iron uptake pathway mediated by high-level expression of transferrin receptor 2 (TFR2). Therefore, growing pigs are employed to investigate the mechanism of TFR2 pathway in hepatic iron overload under chronic stress. RNA-seq technology is used to analyze the difference of hepatic lncRNAs and miRNAs targeted TFR2 under chronic stress. Bioinformatics tools are applied to build the lncRNA-miRNA-TFR2 mRNA regulatory network to explore the post-transcriptionally regulatory mechanism of lncRNAs targeted hepatic TFR2 based on ceRNA crosstalk under chronic stress. Our results will provide new targets and insights into regulation of iron homeostasis in pigs under chronic stress.

猪场集约化生产方式对投入产出比的追求，造成养殖过程中应激源众多，应激现象频发，对猪造成慢性应激。慢性应激可降低猪生产性能，造成肝脏铁过载，诱发氧化应激，进而影响动物健康。申请者在前期工作中发现，慢性应激可导致动物肝脏铁过载，与其肝脏铁摄取蛋白TFR2显著上调密切相关。因此，本研究拟建立生长猪慢性应激模型，深入探讨TFR2信号通路在慢性应激诱发猪肝脏铁过载中的作用机制。应用RNA-seq技术分析慢性应激条件下靶向调控猪肝脏TFR2的差异lncRNAs和miRNAs，构建lncRNA-miRNA-TFR2 mRNA表达调控网络，并解析慢性应激条件下lncRNA基于ceRNA途径转录后调控猪肝脏TFR2的分子机制。本研究将为应激状态下机体铁稳态的调控提供靶点和理论依据。

本研究建立动物慢性应激模型，诱发肝脏铁过载。采用蛋白组学和转录组学对铁过载肝脏差异调控因子（lncRNA和miRNA）和差异蛋白联合分析，研究发现：（1）建立大鼠慢性应激模型，揭示慢性应激可诱发大鼠肝脏铁积聚，导致肝脏氧化应激，肝脏铁积聚与铁转运蛋白TFR2高表达密切相关；（2）运用蛋白组学和转录组学联合分析，构建了两条基于ceRNA调控机制的Acer3—miR-132-3p—Tfr2/Entpd8—miR-212-3p—Tfr2调控网络；（3）明确揭示了α-硫辛酸对铁过载诱导的大鼠肝脏损伤的缓解作用及调节机制。上述结果将为应激状态下动物肝脏铁稳态的调控提供靶点和理论依据。