Hepatic encephalopathy (HE) represents a serious complication of acute liver failure (ALF) in which cerebral edema leading to brainstem herniation as a result of increased intracranial hypertension is a major consequence. Long non-coding RNAs (lncRNAs) play a significant role in coordinating gene expression, with recent studies indicating an influence in the pathogenesis of several diseases.
To investigate their involvement in the cerebral pathophysiology of ALF, researchers from the University of Campinas profiled the expression of lncRNAs in the frontal cortex of mice at coma stage following treatment with the hepatotoxin azoxymethane. Of the 35,923 lncRNAs profiled using microarrays, 868 transcripts were found to be differentially expressed in the ALF-treated group compared to the sham control group. Of these, 382 lncRNAs were upregulated and 486 lncRNAs downregulated. Pathway analysis revealed these lncRNAs target a number of biological and molecular pathways that include cytokine-cytokine receptor interaction, the mitogen activated protein kinase (MAPK) signaling pathway, the insulin signaling pathway, and the NF-kB signaling pathway. False discovery rate adjustment identified 9 upregulated lncRNAs, 2 of which are associated with neuroepithelial transforming gene 1 (NET1) and the monocarboxylate transporter 2 (Slc16a7), potential contributors to astrocyte cytoskeletal disruption/swelling and lactate production, respectively.
Differentially expressed lncRNAs between ALF and sham groups
A) Volcano plot of differentially expressed lncRNAs between the two groups. Red points in the plot represent differentially expressed RNAs with at least a two-fold change and corrected p-value < 0.05. Vertical lines correspond to two-fold upregulation and downregulation, and the horizontal line represents a p-value of 0.05. B) Hierarchical clustering and heat map of lncRNA expression between ALF and sham groups (n = 3 microarrays per group), based on fold-change/probability analysis. C) Signaling pathways associated with upregulated lncRNAs, and D) signaling pathways associated with downregulated lncRNAs. Pathway analysis was predominantly based on the KEGG database. A p-value < 0.05 using the unpaired Student’s t-test was considered as being significant.
These findings suggest an important role for lncRNAs in the brain in relation to inflammation, the neuropathological consequences of ALF, and in terms of the functional basis of HE. Further work on these non-coding RNAs may lead to new therapeutic approaches for the treatment and management of cerebral dysfunction resulting from this potentially life-threatening disorder.