Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA.
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
J Clin Invest. 2021 Apr 1;131(7). doi: 10.1172/JCI140300.
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
肝缺血再灌注（IR）损伤导致与肝移植相关的发病率和死亡率增加。微小 RNA（miRNA）是一类非编码 RNA，通过抑制特定靶基因的翻译来调节基因表达。在这里，我们假设 miRNA 可以作为靶点来增强肝缺血耐受。在肝 IR 损伤的小鼠模型中进行 miRNA 筛选，提示我们注意到肝脏特异性 miRNA miR122。随后在肝特异性 miR122 缺失（miR122loxP/loxP Alb-Cre+ 小鼠）的小鼠中进行的缺血再灌注研究显示肝损伤加重。转录研究表明缺氧诱导因子-1α（HIF1α）在 miR122 的诱导中起作用，并确定氧感应脯氨酰羟化酶结构域 1（PHD1）是 miR122 的靶标。进一步的研究表明，HIF1α 依赖性 miR122 诱导通过 PHD1 抑制增强肝脏 HIF 反应，参与肝脏保护的正反馈途径。此外，利用纳米颗粒介导的 miR122 过表达进行的药理学研究表明肝损伤减轻。最后，在接受原位肝移植的患者中进行的原理验证研究显示，在缺血后的肝活检中，miR122 水平升高，同时 PHD1 受到抑制。总之，这些发现为 miR122 增强肝缺血耐受的功能作用提供了分子见解，并表明针对 miR122 的药理学干预可能具有减弱肝移植期间肝损伤的潜力。
