TY - JOUR TI - Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis AU - Kuo, Andrew AU - Checa, Antonio AU - Niaudet, Colin AU - Jung, Bongnam AU - Fu, Zhongjie AU - Wheelock, Craig E AU - Singh, Sasha A AU - Aikawa, Masanori AU - Smith, Lois E AU - Proia, Richard L AU - Hla, Timothy A2 - Morrisey, Edward E A2 - He, Jinlong VL - 11 PY - 2022 DA - 2022/10/05 SP - e78861 C1 - eLife 2022;11:e78861 DO - 10.7554/eLife.78861 UR - https://doi.org/10.7554/eLife.78861 AB - 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. KW - sphingolipid metabolism KW - angiogenesis KW - lipid homeostasis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -