Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)

Abstract The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and β revealed high docking scores for L3 and D3 hydroxymetabolites, similar to tho...

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Autores principales:	Andrzej T. Slominski, Tae-Kang Kim, Shariq Qayyum, Yuwei Song, Zorica Janjetovic, Allen S. W. Oak, Radomir M. Slominski, Chander Raman, Joanna Stefan, Carlos A. Mier-Aguilar, Venkatram Atigadda, David K. Crossman, Andriy Golub, Yaroslav Bilokin, Edith K. Y. Tang, Jake Y. Chen, Robert C. Tuckey, Anton M. Jetten, Yuhua Song
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/25793fb5b8704b48b8b033ea0ef380e3
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spelling	oai:doaj.org-article:25793fb5b8704b48b8b033ea0ef380e32021-12-02T14:26:19ZVitamin D and lumisterol derivatives can act on liver X receptors (LXRs)10.1038/s41598-021-87061-w2045-2322https://doaj.org/article/25793fb5b8704b48b8b033ea0ef380e32021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87061-whttps://doaj.org/toc/2045-2322Abstract The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and β revealed high docking scores for L3 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second nuclear receptor pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. This was validated by their induction of genes downstream of LXR. L3 and D3-derivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes, and by enhanced expression of LXR target genes. L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and β in LanthaScreen TR-FRET LXRα and β coactivator assays. The majority of metabolites functioned as LXRα/β agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRβ. Molecular dynamics simulations for the selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed different but overlapping interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds.Andrzej T. SlominskiTae-Kang KimShariq QayyumYuwei SongZorica JanjetovicAllen S. W. OakRadomir M. SlominskiChander RamanJoanna StefanCarlos A. Mier-AguilarVenkatram AtigaddaDavid K. CrossmanAndriy GolubYaroslav BilokinEdith K. Y. TangJake Y. ChenRobert C. TuckeyAnton M. JettenYuhua SongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-23 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrzej T. Slominski Tae-Kang Kim Shariq Qayyum Yuwei Song Zorica Janjetovic Allen S. W. Oak Radomir M. Slominski Chander Raman Joanna Stefan Carlos A. Mier-Aguilar Venkatram Atigadda David K. Crossman Andriy Golub Yaroslav Bilokin Edith K. Y. Tang Jake Y. Chen Robert C. Tuckey Anton M. Jetten Yuhua Song Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
description	Abstract The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and β revealed high docking scores for L3 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second nuclear receptor pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. This was validated by their induction of genes downstream of LXR. L3 and D3-derivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes, and by enhanced expression of LXR target genes. L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and β in LanthaScreen TR-FRET LXRα and β coactivator assays. The majority of metabolites functioned as LXRα/β agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRβ. Molecular dynamics simulations for the selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed different but overlapping interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds.
format	article
author	Andrzej T. Slominski Tae-Kang Kim Shariq Qayyum Yuwei Song Zorica Janjetovic Allen S. W. Oak Radomir M. Slominski Chander Raman Joanna Stefan Carlos A. Mier-Aguilar Venkatram Atigadda David K. Crossman Andriy Golub Yaroslav Bilokin Edith K. Y. Tang Jake Y. Chen Robert C. Tuckey Anton M. Jetten Yuhua Song
author_facet	Andrzej T. Slominski Tae-Kang Kim Shariq Qayyum Yuwei Song Zorica Janjetovic Allen S. W. Oak Radomir M. Slominski Chander Raman Joanna Stefan Carlos A. Mier-Aguilar Venkatram Atigadda David K. Crossman Andriy Golub Yaroslav Bilokin Edith K. Y. Tang Jake Y. Chen Robert C. Tuckey Anton M. Jetten Yuhua Song
author_sort	Andrzej T. Slominski
title	Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
title_short	Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
title_full	Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
title_fullStr	Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
title_full_unstemmed	Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
title_sort	vitamin d and lumisterol derivatives can act on liver x receptors (lxrs)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/25793fb5b8704b48b8b033ea0ef380e3
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Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)

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