LncRNA Hnf4αos exacerbates liver ischemia/reperfusion injury in mice via Hnf4αos/Hnf4α duplex-mediated PGC1α suppression

摘要

LncRNAs are involved in the pathophysiologic processes of multiple diseases, but little is known about their functions in hepatic ischemia/reperfusion injury (HIRI). As a novel lncRNA, the pathogenetic significance of hepatic nuclear factor 4 alpha, opposite strand (Hnf4 alpha os) in hepatic I/R injury remains unclear. Here, differ-entially expressed Hnf4 alpha os and Hnf4 alpha antisense RNA 1 (Hnf4 alpha-as1) were identified in liver tissues from mouse ischemia/reperfusion models and patients who underwent liver resection surgery. Hnf4 alpha os deficiency in Hnf4 alpha os- KO mice led to improved liver function, alleviated the inflammatory response and reduced cell death. Mecha-nistically, we found a regulatory role of Hnf4 alpha os-KO in ROS metabolism through PGC1 alpha upregulation. Hnf4 alpha os also promoted the stability of Hnf4 alpha mRNA through an RNA/RNA duplex, leading to the transcriptional acti-vation of miR-23a and miR-23a depletion was required for PGC1 alpha function in hepatoprotective effects on HIRI. Together, our findings reveal that Hnf4 alpha os elevation in HIRI leads to severe liver damage via Hnf4 alpha os/Hnf4 alpha/ miR-23a axis-mediated PGC1 alpha inhibition.

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