Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep17528
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Funding
- Fundacao para a Ciencia e a Tecnologia [PTDC/BIM-MEC/0873/2012]
- [SFRH/BD/88212/2012]
- [SFRH/BD/91119/2012]
- [SFRH/BD/104160/201]
- [UID/DTP/04138/2013]
- Fundação para a Ciência e a Tecnologia [UID/DTP/04138/2013, PTDC/BIM-MEC/0873/2012] Funding Source: FCT
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MicroRNAs (miRNAs/miRs) are key regulators of liver metabolism, while toxic bile acids participate in the development of several liver diseases. We previously demonstrated that deoxycholic acid (DCA), a cytotoxic bile acid implicated in the pathogenesis of non-alcoholic fatty liver disease, inhibits miR-21 expression in hepatocytes. Here, we investigated the mechanisms by which DCA modulates miR-21 and whether miR-21 contributes for DCA-induced cytotoxicity. DCA inhibited miR-21 expression in primary rat hepatocytes in a dose-dependent manner, and increased miR-21 pro-apoptotic target programmed cell death 4 (PDCD4) and apoptosis. Both miR-21 overexpression and PDCD4 silencing hampered DCA-induced cell death. Further, DCA decreased NF-kappa B activity, shown to represent an upstream mechanism leading to modulation of the miR-21/PDCD4 pathway. In fact, NF-kappa B overexpression or constitutive activation halted miR-21-dependent apoptosis by DCA while opposite results were observed upon NF-kappa B inhibition. In turn, DCA-induced oxidative stress resulted in caspase-2 activation and NF-kappa B/miR-21 inhibition, in a PIDD-dependent manner. Finally, modulation of the NF-kappa B/miR-21/PDCD4 pro-apoptotic pathway by DCA was also shown to occur in the rat liver in vivo. These signalling circuits may constitute appealing targets for bile acid-associated liver pathologies.
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