PHD1의 억제에 의한 miR-122의 HIF 유도가 간허혈 관용 향상에 미치는 영향에 관한 연구

Abstract

Hepatic ischemia and reperfusion injury contributes significantly to morbidity and mortality of liver transplantation. MicroRNAs constitute a family of noncoding RNAs that regulate gene expression at the post-translational level through mRNA-repression. Here, we hypothesized that microRNAs could be targeted to enhance hepatic ischemia-tolerance. A targeted microRNA screen in a murine model of liver ischemia demonstrated the largest increase for miR-122 – a liver-specific microRNA implicated in hepatitis C virus propagation. Mice with hepatocyte-specific deletion of miR-122 (miR-122loxp/loxp Alb Cre+ mice) experienced profound ischemic liver injury. Transcriptional studies implicated hypoxia-inducible factor HIF1A in the induction of miR-122, and identified the oxygen-sensing prolyl-hydroxylase PHD1 as novel miR-122 target gene. Further studies indicate that HIF1A-dependent induction of miR-122 participates in a feed-forward pathway for liver protection via enhancing hepatic HIF-responses through PHD1 repression. These findings suggest that pharmacologic approaches promoting miR-122 or repressing PHD1 expression can be targeted therapeutically to enhance hepatic ischemia tolerance.