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Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis

Serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL), is needed for embryonic development, physiological homeostasis, and response to stress. The functions of de novo SL synthesis in vascular endothelial cells (EC), which line the entire circula...

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Autores principales: Kuo, Andrew, Checa, Antonio, Niaudet, Colin, Jung, Bongnam, Fu, Zhongjie, Wheelock, Craig E, Singh, Sasha A, Aikawa, Masanori, Smith, Lois E, Proia, Richard L, Hla, Timothy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578713/
https://www.ncbi.nlm.nih.gov/pubmed/36197001
http://dx.doi.org/10.7554/eLife.78861
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author Kuo, Andrew
Checa, Antonio
Niaudet, Colin
Jung, Bongnam
Fu, Zhongjie
Wheelock, Craig E
Singh, Sasha A
Aikawa, Masanori
Smith, Lois E
Proia, Richard L
Hla, Timothy
author_facet Kuo, Andrew
Checa, Antonio
Niaudet, Colin
Jung, Bongnam
Fu, Zhongjie
Wheelock, Craig E
Singh, Sasha A
Aikawa, Masanori
Smith, Lois E
Proia, Richard L
Hla, Timothy
author_sort Kuo, Andrew
collection PubMed
description Serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL), is needed for embryonic development, physiological homeostasis, and response to stress. The functions of de novo SL synthesis in vascular endothelial cells (EC), which line the entire circulatory system, are not well understood. Here, we show that the de novo SL synthesis in EC not only regulates vascular development but also maintains circulatory and peripheral organ SL levels. Mice with an endothelial-specific gene knockout of SPTLC1 (Sptlc1 ECKO), an essential subunit of the SPT complex, exhibited reduced EC proliferation and tip/stalk cell differentiation, resulting in delayed retinal vascular development. In addition, Sptlc1 ECKO mice had reduced retinal neovascularization in the oxygen-induced retinopathy model. Mechanistic studies suggest that EC SL produced from the de novo pathway are needed for lipid raft formation and efficient VEGF signaling. Post-natal deletion of the EC Sptlc1 also showed rapid reduction of several SL metabolites in plasma, red blood cells, and peripheral organs (lung and liver) but not in the retina, part of the central nervous system (CNS). In the liver, EC de novo SL synthesis was important for acetaminophen-induced rapid ceramide elevation and hepatotoxicity. These results suggest that EC-derived SL metabolites are in constant flux between the vasculature, circulatory elements, and parenchymal cells of non-CNS organs. Taken together, our data point to the central role of the endothelial SL biosynthesis in maintaining vascular development, neovascular proliferation, non-CNS tissue metabolic homeostasis, and hepatocyte response to stress.
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spelling pubmed-95787132022-10-19 Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis Kuo, Andrew Checa, Antonio Niaudet, Colin Jung, Bongnam Fu, Zhongjie Wheelock, Craig E Singh, Sasha A Aikawa, Masanori Smith, Lois E Proia, Richard L Hla, Timothy eLife Cell Biology Serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL), is needed for embryonic development, physiological homeostasis, and response to stress. The functions of de novo SL synthesis in vascular endothelial cells (EC), which line the entire circulatory system, are not well understood. Here, we show that the de novo SL synthesis in EC not only regulates vascular development but also maintains circulatory and peripheral organ SL levels. Mice with an endothelial-specific gene knockout of SPTLC1 (Sptlc1 ECKO), an essential subunit of the SPT complex, exhibited reduced EC proliferation and tip/stalk cell differentiation, resulting in delayed retinal vascular development. In addition, Sptlc1 ECKO mice had reduced retinal neovascularization in the oxygen-induced retinopathy model. Mechanistic studies suggest that EC SL produced from the de novo pathway are needed for lipid raft formation and efficient VEGF signaling. Post-natal deletion of the EC Sptlc1 also showed rapid reduction of several SL metabolites in plasma, red blood cells, and peripheral organs (lung and liver) but not in the retina, part of the central nervous system (CNS). In the liver, EC de novo SL synthesis was important for acetaminophen-induced rapid ceramide elevation and hepatotoxicity. These results suggest that EC-derived SL metabolites are in constant flux between the vasculature, circulatory elements, and parenchymal cells of non-CNS organs. Taken together, our data point to the central role of the endothelial SL biosynthesis in maintaining vascular development, neovascular proliferation, non-CNS tissue metabolic homeostasis, and hepatocyte response to stress. eLife Sciences Publications, Ltd 2022-10-05 /pmc/articles/PMC9578713/ /pubmed/36197001 http://dx.doi.org/10.7554/eLife.78861 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Cell Biology
Kuo, Andrew
Checa, Antonio
Niaudet, Colin
Jung, Bongnam
Fu, Zhongjie
Wheelock, Craig E
Singh, Sasha A
Aikawa, Masanori
Smith, Lois E
Proia, Richard L
Hla, Timothy
Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis
title Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis
title_full Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis
title_fullStr Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis
title_full_unstemmed Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis
title_short Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis
title_sort murine endothelial serine palmitoyltransferase 1 (sptlc1) is required for vascular development and systemic sphingolipid homeostasis
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578713/
https://www.ncbi.nlm.nih.gov/pubmed/36197001
http://dx.doi.org/10.7554/eLife.78861
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