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Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets

Beta cell failure is a critical feature of diabetes. It includes defects of insulin production, secretion, and altered numbers of hormone-producing cells. In previous work, we have shown that beta cell failure is mechanistically linked to loss of Foxo1 function. This loss of function likely results...

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Autores principales: Miyachi, Yasutaka, Kuo, Taiyi, Son, Jinsook, Accili, Domenico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629236/
https://www.ncbi.nlm.nih.gov/pubmed/34843575
http://dx.doi.org/10.1371/journal.pone.0260526
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author Miyachi, Yasutaka
Kuo, Taiyi
Son, Jinsook
Accili, Domenico
author_facet Miyachi, Yasutaka
Kuo, Taiyi
Son, Jinsook
Accili, Domenico
author_sort Miyachi, Yasutaka
collection PubMed
description Beta cell failure is a critical feature of diabetes. It includes defects of insulin production, secretion, and altered numbers of hormone-producing cells. In previous work, we have shown that beta cell failure is mechanistically linked to loss of Foxo1 function. This loss of function likely results from increased Foxo1 protein degradation, due to hyperacetylation of Foxo1 from increased nutrient turnover. To understand the mechanisms of Foxo1-related beta cell failure, we performed genome-wide analyses of its target genes, and identified putative mediators of sub-phenotypes of cellular dysfunction. Chromatin immunoprecipitation analyses demonstrated a striking pattern of Foxo1 binding to the promoters of a cluster of aldo-ketoreductases on chromosome 13: Akr1c12, Akr1c13, Akr1c19. Of these, Akr1c19 has been reported as a marker of Pdx1-positive endodermal progenitor cells. Here we show that Akr1c19 expression is dramatically decreased in db/db islets. Thus, we investigated whether Akr1c19 is involved in beta cell function. We performed gain- and loss-of-function experiments in cultured beta cells and generated Akr1c19 knockout mice. We show that Foxo1 and HNF1a cooperatively regulate Akr1c19 expression. Nonetheless, functional characterization of Akr1c19 both using islets and knockout mice did not reveal abnormalities on glucose homeostasis. We conclude that reduced expression of Akr1c19 is not sufficient to affect islet function.
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spelling pubmed-86292362021-11-30 Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets Miyachi, Yasutaka Kuo, Taiyi Son, Jinsook Accili, Domenico PLoS One Research Article Beta cell failure is a critical feature of diabetes. It includes defects of insulin production, secretion, and altered numbers of hormone-producing cells. In previous work, we have shown that beta cell failure is mechanistically linked to loss of Foxo1 function. This loss of function likely results from increased Foxo1 protein degradation, due to hyperacetylation of Foxo1 from increased nutrient turnover. To understand the mechanisms of Foxo1-related beta cell failure, we performed genome-wide analyses of its target genes, and identified putative mediators of sub-phenotypes of cellular dysfunction. Chromatin immunoprecipitation analyses demonstrated a striking pattern of Foxo1 binding to the promoters of a cluster of aldo-ketoreductases on chromosome 13: Akr1c12, Akr1c13, Akr1c19. Of these, Akr1c19 has been reported as a marker of Pdx1-positive endodermal progenitor cells. Here we show that Akr1c19 expression is dramatically decreased in db/db islets. Thus, we investigated whether Akr1c19 is involved in beta cell function. We performed gain- and loss-of-function experiments in cultured beta cells and generated Akr1c19 knockout mice. We show that Foxo1 and HNF1a cooperatively regulate Akr1c19 expression. Nonetheless, functional characterization of Akr1c19 both using islets and knockout mice did not reveal abnormalities on glucose homeostasis. We conclude that reduced expression of Akr1c19 is not sufficient to affect islet function. Public Library of Science 2021-11-29 /pmc/articles/PMC8629236/ /pubmed/34843575 http://dx.doi.org/10.1371/journal.pone.0260526 Text en © 2021 Miyachi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Miyachi, Yasutaka
Kuo, Taiyi
Son, Jinsook
Accili, Domenico
Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
title Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
title_full Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
title_fullStr Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
title_full_unstemmed Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
title_short Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
title_sort aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629236/
https://www.ncbi.nlm.nih.gov/pubmed/34843575
http://dx.doi.org/10.1371/journal.pone.0260526
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