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Published on: October 21, 2017
Acute liver failure-induced hepatic encephalopathy s associated with changes in microRNA expression rofiles in
Raghu Vemuganti1, Vinícius R Silva, Suresh L Mehta
1Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.
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.
Insights
Altered microRNAs (miRNAs) in the brain during acute liver failure (ALF) may drive neurological dysfunction. These miRNAs target key signaling pathways, suggesting a novel mechanism for ALF-induced brain issues.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Acute liver failure (ALF) causes brain dysfunction, but underlying mechanisms remain unclear.
- MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and are implicated in various physiological and pathological processes.
- Understanding miRNA involvement in ALF-induced neurological deficits is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of microRNAs (miRNAs) in the cerebral cortex during acute liver failure (ALF).
- To identify specific miRNAs and their targeted pathways altered in ALF.
- To explore the potential contribution of these miRNA changes to neurological dysfunction in ALF.
Main Methods:
- Profiling of microRNA expression in the cerebral cortex of mice at the coma stage following azoxymethane-induced ALF.
- Utilizing microarrays for miRNA expression analysis.
- In silico analysis to predict miRNA targets and associated biological pathways.
Main Results:
- 37 out of 470 profiled microRNAs showed significant expression changes in ALF mice compared to controls.
- ALF-responsive miRNAs target numerous mRNAs, impacting key signaling pathways.
- Top targeted pathways include glutamatergic synapse, Wnt signaling, MAP-kinase signaling, and PI3-kinase-AKT signaling.
Conclusions:
- Alterations in microRNA expression are evident in the brain during acute liver failure.
- These dysregulated miRNAs likely influence multiple signaling pathways crucial for neuronal function.
- Changes in miRNA and downstream mRNA expression may contribute to the development and progression of neurological dysfunction in ALF.
