Hepatic Gene Expression Profiles Differentiate Steatotic and Non-steatotic Grafts in Liver Transplant Recipients
Hepatic Gene Expression Profiles Differentiate Steatotic and Non-steatotic Grafts in Liver Transplant Recipients
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DOI：
10.3389/fendo.2019.00270
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发表时间：
2019-04-30
影响因子：
5.2
通讯作者：
Trunecka, Pavel
中科院分区：
文献类型：
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作者：
Seda, Ondrej;Cahova, Monika;Trunecka, Pavel
背景：在高达40%的肝移植受者中，肝移植导致非酒精性脂肪性肝病或非酒精性脂肪性肝炎。我们研究的目的是评估移植肝的转录图谱，并对比移植后脂肪移植和非脂肪移植患者的肝脏基因表达。方法：从91例受者的移植肝活检组织中提取总RNA。对48例脂肪变性患者和43例对照患者的临床特征进行比较。用Affymetrix Geneatas处理的Affymetrix HuGen2.1 ST阵列条带分析它们的转录图谱。结果：肝脏脂肪变性患者存在较高的肥胖指数，包括体重、腰围或BMI，但两组在胰岛素敏感性和胆固醇浓度方面具有可比性。我们已经确定了747个转录本(与对照组相比，脂肪变性样本中326个上调，421个下调)在有脂肪变性的移植物和没有脂肪变性的移植物之间有显著差异。脂肪变性样本中下调最多的基因是P4HA1、IGF1或胎球蛋白B，而上调最多的是PLIN1和ME1。最具影响力的上游监管机构包括HNF1A、RXRA和FXR。脂肪变性肝移植的代谢途径包括凝血、胆汁酸合成和转运、细胞氧化还原动态平衡、脂质和胆固醇代谢、上皮细胞黏附连接信号、氨基酸代谢、AMPK和胰升糖素信号、转甲基化反应和炎症相关途径。脂肪变性样本和对照之间主要转录组差异的衍生机制网络以PPARA和SERPINE1为主要节点。结论：尽管当前研究结果与已发表的非移植肝脂肪变性转录图谱之间存在一定的重叠，但我们已经确定了移植肝中非酒精性脂肪性肝病的离散特征，可能用于建立预测特征。
Background: Liver transplantation leads to non-alcoholic fatty liver disease or nonalcoholic steatohepatitis in up to 40% of graft recipients. The aim of our study was to assess transcriptomic profiles of liver grafts and to contrast the hepatic gene expression between the patients after transplantation with vs. without graft steatosis.Methods: Total RNA was isolated from liver graft biopsies of 91 recipients. Clinical characteristics were compared between steatotic (n = 48) and control (n = 43) samples. Their transcriptomic profiles were assessed using Affymetrix HuGene 2.1 ST Array Strips processed in Affymetrix GeneAtlas. Data were analyzed using Partek Genomics Suite 6.6 and Ingenuity Pathway Analysis.Results: The individuals with hepatic steatosis showed higher indices of obesity including weight, waist circumference or BMI but the two groups were comparable in measures of insulin sensitivity and cholesterol concentrations. We have identified 747 transcripts (326 upregulated and 421 downregulated in steatotic samples compared to controls) significantly differentially expressed between grafts with vs. those without steatosis. Among the most downregulated genes in steatotic samples were P4HA1, IGF1, or fetuin B while the most upregulated were PLIN1 and ME1. Most influential upstream regulators included HNF1A, RXRA, and FXR. The metabolic pathways dysregulated in steatotic liver grafts comprised blood coagulation, bile acid synthesis and transport, cell redox homeostasis, lipid and cholesterol metabolism, epithelial adherence junction signaling, amino acid metabolism, AMPK and glucagon signaling, transmethylation reactions, and inflammation-related pathways. The derived mechanistic network underlying major transcriptome differences between steatotic samples and controls featured PPARA and SERPINE1 as main nodes.Conclusions: While there is a certain overlap between the results of the current study and published transcriptomic profiles of non-transplanted livers with steatosis, we have identified discrete characteristics of the non-alcoholic fatty liver disease in liver grafts potentially utilizable for the establishment of predictive signature.