Ling Q, Xie H, Li J, Liu J, Cao J, Yang F, Wang C, Hu Q, Xu X, Zheng S
Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
Am J Transplant. 2017 Jan;17(1):255-264. doi: 10.1111/ajt.13984. Epub 2016 Sep 7.
New-onset diabetes after liver transplantation (NODALT) is a frequent complication with an unfavorable outcome. We previously demonstrated a crucial link between donor graft genetics and the risk of NODALT. We selected 15 matched pairs of NODALT and non-NODALT liver recipients using propensity score matching analysis. The donor liver tissues were tested for the expression of 10 microRNAs (miRNAs) regulating human hepatic glucose homeostasis. The biological functions of potential target genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Both miR-103 and miR-181a were significantly highly expressed in the NODALT group as compared to the non-NODALT group. The predicted target genes (e.g. Irs2, Pik3r1, Akt2, and Gsk3b) were involved in glucose import and the insulin signaling pathway. We also observed dysregulation of miRNAs (e.g. let-7, miR-26b, miR-145, and miR-183) in cultured human hepatocytes treated with tacrolimus or high glucose, the two independent risk factors of NODALT identified in this cohort. The hepatic miRNA profiles altered by tacrolimus or hyperglycemia were associated with insulin resistance and glucose homeostatic imbalance as revealed by enrichment analysis. The disease susceptibility miRNA expressive pattern could be imported directly from the donor and consolidated by the transplant factors.
肝移植后新发糖尿病（NODALT）是一种常见并发症，预后不佳。我们之前证明了供体移植物遗传学与NODALT风险之间的关键联系。我们使用倾向评分匹配分析选择了15对匹配的NODALT和非NODALT肝移植受者。检测供体肝组织中10种调节人类肝脏葡萄糖稳态的微小RNA（miRNA）的表达。使用基因本体论和京都基因与基因组百科全书（KEGG）富集分析预测潜在靶基因的生物学功能。与非NODALT组相比，miR-103和miR-181a在NODALT组中均显著高表达。预测的靶基因（如Irs2、Pik3r1、Akt2和Gsk3b）参与葡萄糖摄取和胰岛素信号通路。我们还观察到在用他克莫司或高糖处理的培养人肝细胞中miRNA（如let-7、miR-26b、miR-145和miR-183）的失调，他克莫司和高糖是该队列中确定的NODALT的两个独立危险因素。如富集分析所示，他克莫司或高血糖改变的肝脏miRNA谱与胰岛素抵抗和葡萄糖稳态失衡有关。疾病易感性miRNA表达模式可直接从供体导入并由移植因素巩固。
