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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Research Article Gastroenterology Transplantation

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 1

Identification of miR122 as a hypoxia-responsive miRNA during hepatic IR injury.

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Identification of miR122 as a hypoxia-responsive miRNA during hepatic IR...
(A) Targeted miRNA array in WT liver after hepatic ischemia (60 minutes) and reperfusion (6 hours). The data shown indicate fold changes of the indicated miRNAs in mouse livers subjected to IR injury relative to sham control liver tissues. *P < 0.05 compared with values for the WT sham mice indicated by the dashed line, by 2-tailed, unpaired Student’s t test. n = 11/group. (B) Hepatic mmu-miR122 transcript levels following the indicated hepatic ischemia times and a 6-hour reperfusion. Statistical significance was determined by 1-way ANOVA. n = 9/group, except n = 10 in the 30-minute ischemia group. (C) Hepatic mmu-miR122 transcript levels after 60 minutes of liver ischemia and the indicated reperfusion times. Statistical significance was determined by 1-way ANOVA. n = 13, 9, 9, 12, and 5 for 0, 1, 3, 6, and 24 hours, respectively. (D) Hsa-miR122 transcript levels in cultured human hepatocytes (HepG2 cells) exposed to hypoxia (1% oxygen) for the indicated durations. Statistical significance was determined by 1-way ANOVA. n = 12, 12, 11, 11, and 11 for the 0-, 2-, 4-, 8-, and 24-hour groups, respectively). All data are shown as the mean ± SEM.