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Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation

The loss of functional β-cell mass in type 2 diabetes (T2D) is associated with molecular events that include β-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several β-cell functions, including insulin secretion, proliferation and survival....

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Autores principales: Grieco, Giuseppina E., Brusco, Noemi, Fignani, Daniela, Nigi, Laura, Formichi, Caterina, Licata, Giada, Marselli, Lorella, Marchetti, Piero, Salvini, Laura, Tinti, Laura, Po, Agnese, Ferretti, Elisabetta, Sebastiani, Guido, Dotta, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338237/
https://www.ncbi.nlm.nih.gov/pubmed/35906204
http://dx.doi.org/10.1038/s41420-022-01142-x
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author Grieco, Giuseppina E.
Brusco, Noemi
Fignani, Daniela
Nigi, Laura
Formichi, Caterina
Licata, Giada
Marselli, Lorella
Marchetti, Piero
Salvini, Laura
Tinti, Laura
Po, Agnese
Ferretti, Elisabetta
Sebastiani, Guido
Dotta, Francesco
author_facet Grieco, Giuseppina E.
Brusco, Noemi
Fignani, Daniela
Nigi, Laura
Formichi, Caterina
Licata, Giada
Marselli, Lorella
Marchetti, Piero
Salvini, Laura
Tinti, Laura
Po, Agnese
Ferretti, Elisabetta
Sebastiani, Guido
Dotta, Francesco
author_sort Grieco, Giuseppina E.
collection PubMed
description The loss of functional β-cell mass in type 2 diabetes (T2D) is associated with molecular events that include β-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several β-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects β-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in β-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human β-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the β-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects β-cells from apoptosis through a CRTC1-dependent mechanism.
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spelling pubmed-93382372022-07-31 Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation Grieco, Giuseppina E. Brusco, Noemi Fignani, Daniela Nigi, Laura Formichi, Caterina Licata, Giada Marselli, Lorella Marchetti, Piero Salvini, Laura Tinti, Laura Po, Agnese Ferretti, Elisabetta Sebastiani, Guido Dotta, Francesco Cell Death Discov Article The loss of functional β-cell mass in type 2 diabetes (T2D) is associated with molecular events that include β-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several β-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects β-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in β-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human β-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the β-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects β-cells from apoptosis through a CRTC1-dependent mechanism. Nature Publishing Group UK 2022-07-29 /pmc/articles/PMC9338237/ /pubmed/35906204 http://dx.doi.org/10.1038/s41420-022-01142-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Grieco, Giuseppina E.
Brusco, Noemi
Fignani, Daniela
Nigi, Laura
Formichi, Caterina
Licata, Giada
Marselli, Lorella
Marchetti, Piero
Salvini, Laura
Tinti, Laura
Po, Agnese
Ferretti, Elisabetta
Sebastiani, Guido
Dotta, Francesco
Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
title Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
title_full Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
title_fullStr Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
title_full_unstemmed Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
title_short Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
title_sort reduced mir-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via crtc1 upregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338237/
https://www.ncbi.nlm.nih.gov/pubmed/35906204
http://dx.doi.org/10.1038/s41420-022-01142-x
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