Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/16371
Title
Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis
Author(s)
Gomez-Mariano, Gema Maria ISCIII | Perez-Luz, Sara ISCIII | Ramos-Del Saz, Sheila ISCIII | Matamala, Nerea ISCIII | Hernandez-Sanmiguel, Esther ISCIII | Fernandez-Prieto, Marta ISCIII | Gil-Martín, Sara ISCIII | Justo, Iago | Marcacuzco, Alberto | Martinez-Delgado, Beatriz ISCIII
Date issued
2023-08-10
Citation
Int J Mol Sci. 2023 Aug 10;24(16):12645.
Language
Inglés
Document type
research article
Abstract
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.
Subject
Acid sphignoimylinase deficiency (ASMD) | Niemann-Pick type B | Organoids | Liver | Lipids | Lysosome | SMPD1 gene
MESH
Niemann-Pick Disease, Type A | Niemann-Pick Diseases | Humans | Sphingomyelins | Liver | Gene Expression
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DOI
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