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LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces...

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Autores principales: Patel, Deven, Ahmad, Fahim, Kambach, Diane M., Sun, Qian, Halim, Alan S., Kramp, Tamalee, Camphausen, Kevin A., Stommel, Jayne M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820787/
https://www.ncbi.nlm.nih.gov/pubmed/31664073
http://dx.doi.org/10.1038/s41598-019-51865-8
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author Patel, Deven
Ahmad, Fahim
Kambach, Diane M.
Sun, Qian
Halim, Alan S.
Kramp, Tamalee
Camphausen, Kevin A.
Stommel, Jayne M.
author_facet Patel, Deven
Ahmad, Fahim
Kambach, Diane M.
Sun, Qian
Halim, Alan S.
Kramp, Tamalee
Camphausen, Kevin A.
Stommel, Jayne M.
author_sort Patel, Deven
collection PubMed
description Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms.
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spelling pubmed-68207872019-11-04 LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1 Patel, Deven Ahmad, Fahim Kambach, Diane M. Sun, Qian Halim, Alan S. Kramp, Tamalee Camphausen, Kevin A. Stommel, Jayne M. Sci Rep Article Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms. Nature Publishing Group UK 2019-10-29 /pmc/articles/PMC6820787/ /pubmed/31664073 http://dx.doi.org/10.1038/s41598-019-51865-8 Text en © The Author(s) 2019 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/.
spellingShingle Article
Patel, Deven
Ahmad, Fahim
Kambach, Diane M.
Sun, Qian
Halim, Alan S.
Kramp, Tamalee
Camphausen, Kevin A.
Stommel, Jayne M.
LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1
title LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1
title_full LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1
title_fullStr LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1
title_full_unstemmed LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1
title_short LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1
title_sort lxrβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of abca1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820787/
https://www.ncbi.nlm.nih.gov/pubmed/31664073
http://dx.doi.org/10.1038/s41598-019-51865-8
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