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An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cho...

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Autores principales: Talvio, Karo, Wagner, Victoria A., Minkeviciene, Rimante, Kirkwood, Jay S., Kulinich, Anna O., Umemori, Juzoh, Bhatia, Anil, Hur, Manhoi, Käkelä, Reijo, Ethell, Iryna M., Castrén, Maija L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10387075/
https://www.ncbi.nlm.nih.gov/pubmed/37516746
http://dx.doi.org/10.1038/s42003-023-05147-9
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author Talvio, Karo
Wagner, Victoria A.
Minkeviciene, Rimante
Kirkwood, Jay S.
Kulinich, Anna O.
Umemori, Juzoh
Bhatia, Anil
Hur, Manhoi
Käkelä, Reijo
Ethell, Iryna M.
Castrén, Maija L.
author_facet Talvio, Karo
Wagner, Victoria A.
Minkeviciene, Rimante
Kirkwood, Jay S.
Kulinich, Anna O.
Umemori, Juzoh
Bhatia, Anil
Hur, Manhoi
Käkelä, Reijo
Ethell, Iryna M.
Castrén, Maija L.
author_sort Talvio, Karo
collection PubMed
description Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.
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spelling pubmed-103870752023-07-31 An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis Talvio, Karo Wagner, Victoria A. Minkeviciene, Rimante Kirkwood, Jay S. Kulinich, Anna O. Umemori, Juzoh Bhatia, Anil Hur, Manhoi Käkelä, Reijo Ethell, Iryna M. Castrén, Maija L. Commun Biol Article Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS. Nature Publishing Group UK 2023-07-29 /pmc/articles/PMC10387075/ /pubmed/37516746 http://dx.doi.org/10.1038/s42003-023-05147-9 Text en © The Author(s) 2023 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
Talvio, Karo
Wagner, Victoria A.
Minkeviciene, Rimante
Kirkwood, Jay S.
Kulinich, Anna O.
Umemori, Juzoh
Bhatia, Anil
Hur, Manhoi
Käkelä, Reijo
Ethell, Iryna M.
Castrén, Maija L.
An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
title An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
title_full An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
title_fullStr An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
title_full_unstemmed An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
title_short An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
title_sort ipsc-derived astrocyte model of fragile x syndrome exhibits dysregulated cholesterol homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10387075/
https://www.ncbi.nlm.nih.gov/pubmed/37516746
http://dx.doi.org/10.1038/s42003-023-05147-9
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