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@article{1738277, author = {Newton, J. and Palladino, E. N. D. and Weigel, C. and Maceyka, M. and Graler, M. H. and Senkal, C. E. and Enriz, R. D. and Marvanová, Pavlína and Jampilek, J. and Lima, S. and Milstien, S. and Spiegel, S.}, article_location = {Bethesda, USA}, article_number = {27}, doi = {http://dx.doi.org/10.1074/jbc.RA120.012659}, keywords = {sphingosine kinase; cholesterol; Niemann?Pick type C; sphingolipids; lysosomal storage disease; genetic disorder; lipid metabolism; neurodegeneration; sphingolipid; sphingosine kinase (SphK); sphingosine-1-phosphate (S1P); NPC1}, language = {eng}, issn = {0021-9258}, journal = {Journal of Biological Chemistry}, title = {Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation}, url = {https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub}, volume = {295}, year = {2020} }
TY - JOUR ID - 1738277 AU - Newton, J. - Palladino, E. N. D. - Weigel, C. - Maceyka, M. - Graler, M. H. - Senkal, C. E. - Enriz, R. D. - Marvanová, Pavlína - Jampilek, J. - Lima, S. - Milstien, S. - Spiegel, S. PY - 2020 TI - Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation JF - Journal of Biological Chemistry VL - 295 IS - 27 SP - 9121-9133 EP - 9121-9133 PB - Amer. Soc. Biochem. Mol. Biol. SN - 00219258 KW - sphingosine kinase KW - cholesterol KW - Niemann?Pick type C KW - sphingolipids KW - lysosomal storage disease KW - genetic disorder KW - lipid metabolism KW - neurodegeneration KW - sphingolipid KW - sphingosine kinase (SphK) KW - sphingosine-1-phosphate (S1P) KW - NPC1 UR - https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub L2 - https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub N2 - Niemann?Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism. ER -
NEWTON, J., E. N. D. PALLADINO, C. WEIGEL, M. MACEYKA, M. H. GRALER, C. E. SENKAL, R. D. ENRIZ, Pavlína MARVANOVÁ, J. JAMPILEK, S. LIMA, S. MILSTIEN a S. SPIEGEL. Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation. \textit{Journal of Biological Chemistry}. Bethesda, USA: Amer. Soc. Biochem. Mol. Biol., 2020, roč.~295, č.~27, s.~9121-9133. ISSN~0021-9258. Dostupné z: https://dx.doi.org/10.1074/jbc.RA120.012659.
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