Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein.
Lipoapoptosis occurring due to an excess of saturated free fatty acids such as palmitate is a key pathogenic event in the initiation of nonalcoholic fatty liver disease. Palmitate loading of cells activates the endoplasmic reticulum stress response, including induction of the proapoptotic transcript...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4196923?pdf=render |
| _version_ | 1819075996252372992 |
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| author | Yasuhiro Miyamoto Amy S Mauer Swarup Kumar Justin L Mott Harmeet Malhi |
| author_facet | Yasuhiro Miyamoto Amy S Mauer Swarup Kumar Justin L Mott Harmeet Malhi |
| author_sort | Yasuhiro Miyamoto |
| collection | DOAJ |
| description | Lipoapoptosis occurring due to an excess of saturated free fatty acids such as palmitate is a key pathogenic event in the initiation of nonalcoholic fatty liver disease. Palmitate loading of cells activates the endoplasmic reticulum stress response, including induction of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Furthermore, the loss of microRNAs is implicated in regulating apoptosis under conditions of endoplasmic reticulum (ER) stress. The aim of this study was to identify specific microRNAs regulating CHOP expression during palmitate-induced ER stress. Five microRNAs were repressed under palmitate-induced endoplasmic reticulum stress conditions in hepatocyte cell lines (miR-92b-3p, miR-328-3p, miR-484, miR-574-5p, and miR-615-3p). We identified miR-615-3p as a candidate microRNA which was repressed by palmitate treatment and regulated CHOP protein expression, by RNA sequencing and in silico analyses, respectively. There is a single miR-615-3p binding site in the 3'untranslated region (UTR) of the Chop transcript. We characterized this as a functional binding site using a reporter gene-based assay. Augmentation of miR-615-3p levels, using a precursor molecule, repressed CHOP expression; and under these conditions palmitate- or tunicamycin-induced cell death were significantly reduced. Our results suggest that palmitate-induced apoptosis requires maximal expression of CHOP which is achieved via the downregulation of its repressive microRNA, miR-615-3p. We speculate that enhancement of miR-615-3p levels may be of therapeutic benefit by inhibiting palmitate-induced hepatocyte lipoapoptosis. |
| first_indexed | 2024-12-21T18:34:17Z |
| format | Article |
| id | doaj.art-151f2e3866a0484190884145014b9d11 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T18:34:17Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-151f2e3866a0484190884145014b9d112022-12-21T18:54:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e10963710.1371/journal.pone.0109637Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein.Yasuhiro MiyamotoAmy S MauerSwarup KumarJustin L MottHarmeet MalhiLipoapoptosis occurring due to an excess of saturated free fatty acids such as palmitate is a key pathogenic event in the initiation of nonalcoholic fatty liver disease. Palmitate loading of cells activates the endoplasmic reticulum stress response, including induction of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Furthermore, the loss of microRNAs is implicated in regulating apoptosis under conditions of endoplasmic reticulum (ER) stress. The aim of this study was to identify specific microRNAs regulating CHOP expression during palmitate-induced ER stress. Five microRNAs were repressed under palmitate-induced endoplasmic reticulum stress conditions in hepatocyte cell lines (miR-92b-3p, miR-328-3p, miR-484, miR-574-5p, and miR-615-3p). We identified miR-615-3p as a candidate microRNA which was repressed by palmitate treatment and regulated CHOP protein expression, by RNA sequencing and in silico analyses, respectively. There is a single miR-615-3p binding site in the 3'untranslated region (UTR) of the Chop transcript. We characterized this as a functional binding site using a reporter gene-based assay. Augmentation of miR-615-3p levels, using a precursor molecule, repressed CHOP expression; and under these conditions palmitate- or tunicamycin-induced cell death were significantly reduced. Our results suggest that palmitate-induced apoptosis requires maximal expression of CHOP which is achieved via the downregulation of its repressive microRNA, miR-615-3p. We speculate that enhancement of miR-615-3p levels may be of therapeutic benefit by inhibiting palmitate-induced hepatocyte lipoapoptosis.http://europepmc.org/articles/PMC4196923?pdf=render |
| spellingShingle | Yasuhiro Miyamoto Amy S Mauer Swarup Kumar Justin L Mott Harmeet Malhi Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PLoS ONE |
| title | Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. |
| title_full | Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. |
| title_fullStr | Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. |
| title_full_unstemmed | Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. |
| title_short | Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. |
| title_sort | mmu mir 615 3p regulates lipoapoptosis by inhibiting c ebp homologous protein |
| url | http://europepmc.org/articles/PMC4196923?pdf=render |
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