Hypoxia-inducible factor–1α–dependent induction of miR122 enhances hepatic ischemia tolerance
Cynthia Ju, … , Kalpana Ghoshal, Holger K. Eltzschig
Cynthia Ju, … , Kalpana Ghoshal, Holger K. Eltzschig
Published April 1, 2021
Citation Information: J Clin Invest. 2021;131(7):e140300. https://doi.org/10.1172/JCI140300.
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Hypoxia-inducible factor–1α–dependent induction of miR122 enhances hepatic ischemia tolerance

Abstract

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.

Authors

Cynthia Ju, Meng Wang, Eunyoung Tak, Boyun Kim, Christoph Emontzpohl, Yang Yang, Xiaoyi Yuan, Huban Kutay, Yafen Liang, David R. Hall, Wasim A. Dar, J. Steve Bynon, Peter Carmeliet, Kalpana Ghoshal, Holger K. Eltzschig

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Figure 5

Hepatic overexpression of miR122 provides liver protection during hepatic IR injury.

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Hepatic overexpression of miR122 provides liver protection during hepati...
(A) Male C57Bl/6 WT mice were injected intravenously with a single dose of 20 μg synthetic mouse miR122 or scrambled miR formulated in NLE, 24 hours prior to 60 minutes of ischemia followed by 6 hours and 24 hours of reperfusion. (B) Treatment of exogenous miR122 increased miR122 levels in sham and IR livers. Two-way ANOVA. n = 6/group in the sham groups, n = 8/group in the IR groups. Mice treated with the miR122 mimetic show decreased levels of ALT (C), AST (D), and LDH (E) following 6 hours of reperfusion. Two-tailed, unpaired Student’s t test. n = 9/group. (F and G) Exogenous miR122 treatment improved histology scores following 24 hours of reperfusion. Two-tailed, unpaired Student’s t test. n = 6/group. (H–L) Exogenous miR122 treatment (H) decreased hepatic PHD1 transcript levels (n = 8/group in the sham groups, n = 9/group in the IR groups), (I and J) augmented stabilization of HIF1α (n = 6, 5 in the scrambled miR and miR122 groups, respectively), and (K and L) repressed PHD1 protein levels (n = 8/group) after liver IR injury. Two-way ANOVA (H) and 2-tailed, unpaired Student’s t test (J and L).