Acute liver failure-induced hepatic encephalopathy s associated with changes in microRNA expression rofiles in cerebral cortex of the mouse [corrected

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.