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Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis
Rationale: Statin, the most widely used medication in lowering cholesterol, is also associated with increased risk of type 2 diabetes, but its molecular basis remains unclear. Methods: Mice were injected intraperitoneally with statins alone or in combination with sirtuin (Sirt) 6 activator, and bloo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545997/ https://www.ncbi.nlm.nih.gov/pubmed/33052223 http://dx.doi.org/10.7150/thno.49770 |
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author | Shi, Min Yan Bang, In Hyuk Han, Chang Yeob Lee, Dae Ho Park, Byung-Hyun Bae, Eun Ju |
author_facet | Shi, Min Yan Bang, In Hyuk Han, Chang Yeob Lee, Dae Ho Park, Byung-Hyun Bae, Eun Ju |
author_sort | Shi, Min Yan |
collection | PubMed |
description | Rationale: Statin, the most widely used medication in lowering cholesterol, is also associated with increased risk of type 2 diabetes, but its molecular basis remains unclear. Methods: Mice were injected intraperitoneally with statins alone or in combination with sirtuin (Sirt) 6 activator, and blood glucose levels were measured. Liver tissues from patients with statin use were analyzed for the expression of Sirt6. Results: Statin treatment up-regulated the hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which was prevented by Sirt6 overexpression. Mechanistically, statin directly repressed Sirt6 expression by induction of microRNA (miR)-495, a novel inhibitor of Sirt6. Pathway analysis for predicted target genes of miR-495 recognized forkhead box protein (Fox)O1 as a key downstream signaling of Sirt6. Statin treatment increased the acetylation and protein stability of FoxO1, which was suppressed by Sirt6 overexpression. Inhibiting miR-495 recovered Sirt6 levels, blocking the ability of statin to increase FoxO1 mediated gluconeogenesis, and thus confirming the role of the miR-495/Sirt6/FoxO1 pathway in controlling gluconeogenesis. Moreover, the Sirt6 activator MDL801 prevented gluconeogenesis and hyperglycemia induced by statin in mice. Equally noteworthy was that human liver tissues obtained from statin users showed a significant decrease in Sirt6 protein levels compared to those of non-users. Conclusion: Statin induces miR-495 to suppress Sirt6 expression, which leads to enhancement of FoxO1-mediated hepatic gluconeogenesis. Thus, Sirt6 activation may offer a promising strategy for preventing statin-induced hyperglycemia. |
format | Online Article Text |
id | pubmed-7545997 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-75459972020-10-12 Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis Shi, Min Yan Bang, In Hyuk Han, Chang Yeob Lee, Dae Ho Park, Byung-Hyun Bae, Eun Ju Theranostics Research Paper Rationale: Statin, the most widely used medication in lowering cholesterol, is also associated with increased risk of type 2 diabetes, but its molecular basis remains unclear. Methods: Mice were injected intraperitoneally with statins alone or in combination with sirtuin (Sirt) 6 activator, and blood glucose levels were measured. Liver tissues from patients with statin use were analyzed for the expression of Sirt6. Results: Statin treatment up-regulated the hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which was prevented by Sirt6 overexpression. Mechanistically, statin directly repressed Sirt6 expression by induction of microRNA (miR)-495, a novel inhibitor of Sirt6. Pathway analysis for predicted target genes of miR-495 recognized forkhead box protein (Fox)O1 as a key downstream signaling of Sirt6. Statin treatment increased the acetylation and protein stability of FoxO1, which was suppressed by Sirt6 overexpression. Inhibiting miR-495 recovered Sirt6 levels, blocking the ability of statin to increase FoxO1 mediated gluconeogenesis, and thus confirming the role of the miR-495/Sirt6/FoxO1 pathway in controlling gluconeogenesis. Moreover, the Sirt6 activator MDL801 prevented gluconeogenesis and hyperglycemia induced by statin in mice. Equally noteworthy was that human liver tissues obtained from statin users showed a significant decrease in Sirt6 protein levels compared to those of non-users. Conclusion: Statin induces miR-495 to suppress Sirt6 expression, which leads to enhancement of FoxO1-mediated hepatic gluconeogenesis. Thus, Sirt6 activation may offer a promising strategy for preventing statin-induced hyperglycemia. Ivyspring International Publisher 2020-09-15 /pmc/articles/PMC7545997/ /pubmed/33052223 http://dx.doi.org/10.7150/thno.49770 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Shi, Min Yan Bang, In Hyuk Han, Chang Yeob Lee, Dae Ho Park, Byung-Hyun Bae, Eun Ju Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis |
title | Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis |
title_full | Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis |
title_fullStr | Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis |
title_full_unstemmed | Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis |
title_short | Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis |
title_sort | statin suppresses sirtuin 6 through mir-495, increasing foxo1-dependent hepatic gluconeogenesis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545997/ https://www.ncbi.nlm.nih.gov/pubmed/33052223 http://dx.doi.org/10.7150/thno.49770 |
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