Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats.
Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats.
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转录组学揭示大鼠慢加急性肝衰竭的免疫代谢紊乱
DOI：
10.26508/lsa.202101189
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发表时间：
2022-03
影响因子：
4.4
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Hassan HM;Cai Q;Liang X;Xin J;Ren K;Jiang J;Shi D;Lu Y;Li T;Shang Y;He L;Chen X;Sun S;Li P;Guo B;Chen J;Yang H;Hu W;Chen X;Li J
以肝硬变(LC)为基础的急性-慢性肝衰竭(ACLF)大鼠的肝组织转录组研究表明，免疫代谢紊乱是ACLF发生和预后的核心机制。急性-慢性肝衰竭(ACLF)是一种病死率较高的临床综合征。本研究旨在对基于肝硬变的ACLF大鼠进行详细的转录分析，以阐明ACLF的发病机制。用猪血清、D-氨基半乳糖和脂多糖联合诱导ACLF。用转录组测序的方法获得ACLF大鼠肝组织的基因表达谱，以揭示其分子机制。ACLF大鼠发育成功，具有典型特征。当ACLF分别与肝硬变和正常对照组比较时，共鉴定出2354/3576个差异表达基因。功能协同分析显示ACLF期免疫功能紊乱显著，而代谢紊乱显著下调。先天免疫相关细胞的相对比例表现为单核细胞和巨噬细胞显著增加，而获得性免疫相关细胞减少。对ACLF分子机制的7个差异表达基因进行了外部验证，其中THBS1、IL-10和NR4A3在大鼠、患者转录本和肝活检中的表达得到证实，验证了它们在ACLF发病机制中的潜在价值。本研究提示ACLF大鼠存在免疫代谢紊乱，这可能为临床医生改进干预策略提供新的靶点。
Liver tissue transcriptomics of liver cirrhosis (LC)–based acute-on-chronic liver failure (ACLF) rats reveal immune-metabolism disorder as the core mechanism underlying ACLF development and prognosis. Acute-on-chronic liver failure (ACLF) is clinical syndrome with high mortality rate. This study aimed to perform detailed transcriptomic analysis in liver cirrhosis–based ACLF rats to elucidate ACLF pathogenesis. ACLF was induced by combined porcine serum with D-galactosamine and lipopolysaccharide. Gene expression profile of liver tissues from ACLF rats was generated by transcriptome sequencing to reveal the molecular mechanism. ACLF rats successfully developed with typical characteristics. Total of 2,354/3,576 differentially expressed genes were identified when ACLF was compared to liver cirrhosis and normal control, separately. The functional synergy analysis revealed prominent immune dysregulation at ACLF stage, whereas metabolic disruption was significantly down-regulated. Relative proportions of innate immune–related cells showed significant elevation of monocytes and macrophages, whereas adaptive immune–related cells were reduced. The seven differentially expressed genes underlying the ACLF molecular mechanisms were externally validated, among them THBS1, IL-10, and NR4A3 expressions were confirmed in rats, patient transcriptomics, and liver biopsies, verifying their potential value in the ACLF pathogenesis. This study indicates immune-metabolism disorder in ACLF rats, which may provide clinicians new targets for improving intervention strategies.