Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neur...
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/11/9756 |
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| author | Ángel Gaudioso Pilar Moreno-Huguet Josefina Casas Edward H. Schuchman María Dolores Ledesma |
| author_facet | Ángel Gaudioso Pilar Moreno-Huguet Josefina Casas Edward H. Schuchman María Dolores Ledesma |
| author_sort | Ángel Gaudioso |
| collection | DOAJ |
| description | Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neuroinflammation and neurodegeneration for which there is no effective treatment. Cellular accumulation of sphingomyelin (SM) is a pathological hallmark in all tissues. SM is the only sphingolipid comprised of a phosphocholine group linked to ceramide. Choline is an essential nutrient that must be obtained from the diet and its deficiency promotes fatty liver disease in a process dependent on ASM activity. We thus hypothesized that choline deprivation could reduce SM production and have beneficial effects in ASMD. Using acid sphingomyelinase knock-out (ASMko) mice, which mimic neurovisceral ASMD, we have assessed the safety of a choline-free diet and its effects on liver and brain pathological features such as altered sphingolipid and glycerophospholipid composition, inflammation and neurodegeneration. We found that the choline-free diet was safe in our experimental conditions and reduced activation of macrophages and microglia in the liver and brain, respectively. However, there was no significant impact on sphingolipid levels and neurodegeneration was not prevented, arguing against the potential of this nutritional strategy to assist in the management of neurovisceral ASMD patients. |
| first_indexed | 2024-03-11T03:04:46Z |
| format | Article |
| id | doaj.art-890df6f38453443583dfc676d7378a27 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:04:46Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-890df6f38453443583dfc676d7378a272023-11-18T08:03:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-012411975610.3390/ijms24119756Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase DeficiencyÁngel Gaudioso0Pilar Moreno-Huguet1Josefina Casas2Edward H. Schuchman3María Dolores Ledesma4Centro Biologia Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, SpainCentro Biologia Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, SpainRUBAM, IQAC-CSIC & CIBEREHD, 08034 Barcelona, SpainIcahn School of Medicine at Mount Sinai, New York, NY 10029, USACentro Biologia Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, SpainAcid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neuroinflammation and neurodegeneration for which there is no effective treatment. Cellular accumulation of sphingomyelin (SM) is a pathological hallmark in all tissues. SM is the only sphingolipid comprised of a phosphocholine group linked to ceramide. Choline is an essential nutrient that must be obtained from the diet and its deficiency promotes fatty liver disease in a process dependent on ASM activity. We thus hypothesized that choline deprivation could reduce SM production and have beneficial effects in ASMD. Using acid sphingomyelinase knock-out (ASMko) mice, which mimic neurovisceral ASMD, we have assessed the safety of a choline-free diet and its effects on liver and brain pathological features such as altered sphingolipid and glycerophospholipid composition, inflammation and neurodegeneration. We found that the choline-free diet was safe in our experimental conditions and reduced activation of macrophages and microglia in the liver and brain, respectively. However, there was no significant impact on sphingolipid levels and neurodegeneration was not prevented, arguing against the potential of this nutritional strategy to assist in the management of neurovisceral ASMD patients.https://www.mdpi.com/1422-0067/24/11/9756cholinesphingomyelinlysosomal storage disorderlipidomicacid sphingomyelinase deficiencyphospholipid |
| spellingShingle | Ángel Gaudioso Pilar Moreno-Huguet Josefina Casas Edward H. Schuchman María Dolores Ledesma Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency International Journal of Molecular Sciences choline sphingomyelin lysosomal storage disorder lipidomic acid sphingomyelinase deficiency phospholipid |
| title | Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency |
| title_full | Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency |
| title_fullStr | Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency |
| title_full_unstemmed | Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency |
| title_short | Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency |
| title_sort | modulation of dietary choline uptake in a mouse model of acid sphingomyelinase deficiency |
| topic | choline sphingomyelin lysosomal storage disorder lipidomic acid sphingomyelinase deficiency phospholipid |
| url | https://www.mdpi.com/1422-0067/24/11/9756 |
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