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Acute liver failure-induced hepatic encephalopathy is associated with changes in microRNA expression profiles in cerebral cortex of the rat

An Erratum to this article was published on 25 December 2014

Abstract

The mechanisms that promote brain dysfunction after acute liver failure (ALF) are not clearly understood. The small noncoding RNAs known as microRNAs (miRNAs) significantly control mRNA translation and thus normal and pathological functions in the mammalian body. To understand their significance in ALF, we currently profiled the expression of miRNAs in the cerebral cortex of mice sacrificed at coma stage following treatment with azoxymethane. Of the 470 miRNAs profiled using microarrays, 37 were significantly altered (20 up-and 17 down-regulated) in their expression in the ALF group compared to sham group. In silico analysis showed that the ALF-responsive miRNAs target on average 231 mRNAs/miRNA (range: 3 to 840 targets). Pathways analysis showed that many miRNAs altered after ALF target multiple mRNAs that are part of various biological and molecular pathways. Glutamatergic synapse, Wnt signaling, MAP-kinase signaling, axon guidance, PI3-kinase-AKT signaling, T-cell receptor signaling and ubiquitin-mediated proteolysis are the top pathways targeted by the ALF-sensitive miRNAs. At least 28 ALF-responsive miRNAs target each of the above pathways. We hypothesize that alterations in miRNAs and their down-stream mRNAs of signaling pathways might play a role in the induction and progression of neurological dysfunction observed during ALF.

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Acknowledgments

This study was partially supported by a grant (2011/02263-3) to ASH from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). RV is partially supported by NIH grants NS074444, NS079585, NS 082957 and NS083007 and the Department of Neurological Surgery, University of Wisconsin Medical School. VRS is the recipient of a doctoral scholarship from FAPESP (2012/15660-3). ASH is a Visiting Professor in the Department of Neurology at Universidade Estadual de Campinas (UNICAMP), São Paulo, Brazil. His laboratory at the University of Montreal is supported by the Canadian Institutes of Health Research.

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Correspondence to Alan S. Hazell.

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Vemuganti, R., Silva, V.R., Mehta, S.L. et al. Acute liver failure-induced hepatic encephalopathy is associated with changes in microRNA expression profiles in cerebral cortex of the rat. Metab Brain Dis 29, 891–899 (2014). https://doi.org/10.1007/s11011-014-9545-0

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Keywords

  • Liver disease
  • miRNA
  • Non-coding RNA
  • Hepatic encephalopathy
  • Neuroprotection, Molecular signaling