Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis

Acid sphingomyelinase deficiency (ASMD) or Niemann–Pick disease type A (NPA), type B (NPB) and type A/B (NPA/B), is a rare lysosomal storage disease characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was est...

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Autores: Pérez Luz, Sara, Gómez Mariano, Gema, Ramos del Saz, Sheila, Matamala, Nerea, Hernández Sanmiguel, Esther, Fernández Prieto, Marta, Gil Martín, Sara, Justo Alonso, Iago, Marcacuzco Quinto, Alberto Alejandro, Martínez Delgado, Beatriz
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/102012
Acceso en línea:https://hdl.handle.net/20.500.14352/102012
Access Level:acceso abierto
Palabra clave:572.1/.4
Acid sphignoimylinase deficiency (ASMD)
Niemann–Pick type B
Organoids
Liver
Lipids
Lysosome
SMPD1 gene
Biología
2410.07 Genética Humana
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oai_identifier_str oai:docta.ucm.es:20.500.14352/102012
network_acronym_str ES
network_name_str España
repository_id_str
spelling Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid HomeostasisPérez Luz, SaraGómez Mariano, GemaRamos del Saz, SheilaMatamala, NereaHernández Sanmiguel, EstherFernández Prieto, MartaGil Martín, SaraJusto Alonso, IagoMarcacuzco Quinto, Alberto AlejandroMartínez Delgado, Beatriz572.1/.4Acid sphignoimylinase deficiency (ASMD)Niemann–Pick type BOrganoidsLiverLipidsLysosomeSMPD1 geneBiología2410.07 Genética HumanaAcid sphingomyelinase deficiency (ASMD) or Niemann–Pick disease type A (NPA), type B (NPB) and type A/B (NPA/B), is a rare lysosomal storage disease characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was established by generating liver organoids from a NPB patient carrying the p.Arg610del variant in the SMPD1 gene. Liver organoids were characterized by transcriptomic and lipidomic analysis. We observed altered lipid homeostasis in the patient-derived organoids showing the predictable increase in sphingomyelin (SM), together with cholesterol esters (CE) and triacylglycerides (TAG), and a reduction in phosphatidylcholine (PC) and cardiolipins (CL). Analysis of lysosomal gene expression pointed to 24 downregulated genes, including SMPD1, and 26 upregulated genes that reflect the lysosomal stress typical of the disease. Altered genes revealed reduced expression of enzymes that could be involved in the accumulation in the hepatocytes of sphyngoglycolipids and glycoproteins, as well as upregulated genes coding for different glycosidases and cathepsins. Lipidic and transcriptome changes support the use of hepatic organoids as ideal models for ASMD investigation.MDPIUniversidad Complutense de Madrid20232023-08-1020232023-08-10journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/102012reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1020122026-06-02T12:44:21Z
dc.title.none.fl_str_mv Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
title Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
spellingShingle Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
Pérez Luz, Sara
572.1/.4
Acid sphignoimylinase deficiency (ASMD)
Niemann–Pick type B
Organoids
Liver
Lipids
Lysosome
SMPD1 gene
Biología
2410.07 Genética Humana
title_short Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
title_full Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
title_fullStr Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
title_full_unstemmed Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
title_sort Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
dc.creator.none.fl_str_mv Pérez Luz, Sara
Gómez Mariano, Gema
Ramos del Saz, Sheila
Matamala, Nerea
Hernández Sanmiguel, Esther
Fernández Prieto, Marta
Gil Martín, Sara
Justo Alonso, Iago
Marcacuzco Quinto, Alberto Alejandro
Martínez Delgado, Beatriz
author Pérez Luz, Sara
author_facet Pérez Luz, Sara
Gómez Mariano, Gema
Ramos del Saz, Sheila
Matamala, Nerea
Hernández Sanmiguel, Esther
Fernández Prieto, Marta
Gil Martín, Sara
Justo Alonso, Iago
Marcacuzco Quinto, Alberto Alejandro
Martínez Delgado, Beatriz
author_role author
author2 Gómez Mariano, Gema
Ramos del Saz, Sheila
Matamala, Nerea
Hernández Sanmiguel, Esther
Fernández Prieto, Marta
Gil Martín, Sara
Justo Alonso, Iago
Marcacuzco Quinto, Alberto Alejandro
Martínez Delgado, Beatriz
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 572.1/.4
Acid sphignoimylinase deficiency (ASMD)
Niemann–Pick type B
Organoids
Liver
Lipids
Lysosome
SMPD1 gene
Biología
2410.07 Genética Humana
topic 572.1/.4
Acid sphignoimylinase deficiency (ASMD)
Niemann–Pick type B
Organoids
Liver
Lipids
Lysosome
SMPD1 gene
Biología
2410.07 Genética Humana
description Acid sphingomyelinase deficiency (ASMD) or Niemann–Pick disease type A (NPA), type B (NPB) and type A/B (NPA/B), is a rare lysosomal storage disease characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, in severe cases, neurons. A disease model was established by generating liver organoids from a NPB patient carrying the p.Arg610del variant in the SMPD1 gene. Liver organoids were characterized by transcriptomic and lipidomic analysis. We observed altered lipid homeostasis in the patient-derived organoids showing the predictable increase in sphingomyelin (SM), together with cholesterol esters (CE) and triacylglycerides (TAG), and a reduction in phosphatidylcholine (PC) and cardiolipins (CL). Analysis of lysosomal gene expression pointed to 24 downregulated genes, including SMPD1, and 26 upregulated genes that reflect the lysosomal stress typical of the disease. Altered genes revealed reduced expression of enzymes that could be involved in the accumulation in the hepatocytes of sphyngoglycolipids and glycoproteins, as well as upregulated genes coding for different glycosidases and cathepsins. Lipidic and transcriptome changes support the use of hepatic organoids as ideal models for ASMD investigation.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-08-10
2023
2023-08-10
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/102012
url https://hdl.handle.net/20.500.14352/102012
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405695740215296
score 15,301629

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