高原低氧抑制PPAR通路诱导小鼠脾脏铁死亡发生  

High-altitude hypoxia inhibits PPAR pathway induced ferroptosis in spleen of mice

作　　者：王嘉阳 胡英 许玉珍 龙启福[1] 唐超群[1] 永胜 WANG Jiayang;HU Ying;XU Yuzhen;LONG Qifu;TANG Chaoqun;YONG Sheng(Department of Basic Medicine,Qinghai University,Xining 810016,China;Department of Clinical Laboratory,980 Hospital of Chinese Joint Logistic Support Force,Shijiazhuang 050000,China)

机构地区：[1]青海大学基础医学部,西宁810016 [2]联勤保障部队第九八〇医院检验科,石家庄050000

出　　处：《中国免疫学杂志》2025年第2期263-270,共8页Chinese Journal of Immunology

基　　金：国家自然科学基金地区科学基金(82060295);青海省科技计划项目基金(2023-ZJ-771);青海大学青年科研基金项目(2021-QNY-10)。

摘　　要：目的:探究高原低氧调控PPAR信号通路诱导脾脏组织铁死亡发生的分子机制。方法:构建低氧动物模型,通过转录组学和蛋白质组学联合分析筛选预测靶基因,通过GO和KEGG富集分析挖掘低氧暴露下PPAR和铁死亡通路中的关键基因,并通过RT-qPCR和Western blot进行验证。结果:转录组学与蛋白质组学联合分析显示低氧暴露下有95个预测靶基因(蛋白)出现显著差异表达,GO注释分析和KEGG富集分析显示差异基因主要显著富集于PPAR和铁死亡信号通路。PPAR与铁死亡信号通路结果呈负相关,且GSEA显示PPAR和铁死亡信号通路差异基因集在高原低氧组呈相反表达趋势。对PPAR信号通路关键基因PPARA、RXRB、APOA1和SCD-1进行验证,结果发现低氧暴露下其mRNA和蛋白表达均下调。铁死亡信号通路中内源性途径GPX4和外源性途径SLC7A11、TRP53和TFRC mRNA和蛋白均出现差异表达。4个铁死亡关键基因与差异炎症相关基因(DE-IRGs)均呈正相关或负相关。低氧暴露下脾组织中IL-1β、IL-6、IL-12、IL-18、IFN-γ和TNF-α表达上调。结论:高原低氧暴露通过PPAR信号通路介导脂代谢紊乱进一步诱导铁死亡,并伴随炎症反应发生,进而引起脾脏组织损伤。Objective:To explore molecular mechanism of high-altitude hypoxia regulates PPAR signaling pathway induced ferroptosis in spleen.Methods:Hypoxia animal model was constructed,target genes were screened and predicted by combination of transcriptomics and protein omics.Key genes in PPAR and ferroptosis pathways under hypoxia exposure were explored by GO and KEGG enrichment analysis and verified by RT-qPCR and Western blot.Results:Combination of transcriptomics and protein omics showed that 95 predicted target genes(protein)showed significantly differential expression under hypoxic exposure.GO annotation analysis and KEGG enrichment analysis showed that differential genes were mainly significantly enriched in PPAR and ferroptosis signaling pathways.A negative correlation was found between PPAR and ferroptosis signaling pathways,and GSEA showed that differential gene sets of PPAR and ferroptosis signaling pathways exhibited opposite expression trend in high-altitude hypoxia group.Validation of key genes PPARA,RXRB,APOA1 and SCD-1 in PPAR signaling pathway revealed that both mRNA and protein expressions were down-regulated under hypoxic exposure.Subsequently,differential expression was observed in mRNA and protein expressions of GPX4 in endogenous pathway and SLC7A11,TRP53 and TFRC in exogenous pathway in ferroptosis signaling pathway.Correlations between four key genes for ferroptosis and differential inflammation-associated genes(DE-IRGs)were positively or negatively.IL-1β,IL-6,IL-12,IL-18,IFN-γand TNF-αexpressions in spleen tissue were up-regulated under hypoxic exposure.Conclusion:High-altitude hypoxia exposure further induces ferroptosis through PPAR signaling pathway-mediated lipid metabolism disorders,and accompanied by occurrence of inflammatory response,which causes damage of spleen tissue.

关 键 词：高原低氧 脾脏 铁死亡 PPAR信号通路 

分 类 号：R392.1[医药卫生—免疫学]