ArticleCirculation research2010
FTY720 stimulates 27-hydroxycholesterol production and confers atheroprotective effects in human primary macrophages.
Article in Circulation research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
20 citing papers in PubMed, 50 citations in OpenAlex.
- Bioactive Sphingolipids as Major Regulators of Coronary Artery Disease.Biomolecules & therapeutics · 2021Review
- Microglial Phagocytosis-Rational but Challenging Therapeutic Target in Multiple Sclerosis.International journal of molecular sciences · 2020Review
- Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases.Journal of lipid research · 2020Review
- HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo.Molecular metabolism · 2019Article
- Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells.Bioscience reports · 2019Article
- The physiology of foamy phagocytes in multiple sclerosis.Acta neuropathologica communications · 2018Review
- Rapamycin and FTY720 Alleviate Atherosclerosis by Cross Talk of Macrophage Polarization and Autophagy.BioMed research international · 2018Article
- Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget.Oncotarget · 2017Review
- FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Importance of Apolipoprotein A-I in Multiple Sclerosis.Frontiers in pharmacology · 2015Review
- The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction.Journal of cardiovascular pharmacology · 2014Article
- Sphingosine kinase and sphingosine 1-phosphate in the heart: a decade of progress.Biochimica et biophysica acta · 2013Review
- High density lipoproteins and atherosclerosis: emerging aspects.Journal of geriatric cardiology : JGC · 2012Article
- Sphingosine-1-phosphate signaling and its role in disease.Trends in cell biology · 2012Review
- Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2.Cellular and molecular neurobiology · 2011Article
- Pharmacological modulation of cell death in atherosclerosis: a promising approach towards plaque stabilization?British journal of pharmacology · 2011Review
- Selectivity and specificity of sphingosine-1-phosphate receptor ligands: caveats and critical thinking in characterizing receptor-mediated effects.Frontiers in pharmacology · 2011Article
- Kdo2-lipid A, a TLR4-specific agonist, induces de novo sphingolipid biosynthesis in RAW264.7 macrophages, which is essential for induction of autophagy.The Journal of biological chemistry · 2010Article
- Genetic connections between neurological disorders and cholesterol metabolism.Journal of lipid research · 2010Article
- HDL-cholesterol elevation associated with fingolimod and dimethyl fumarate therapies in multiple sclerosis.Multiple sclerosis journal - experimental, translational and clinicalArticle
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
rationaleThe synthetic sphingosine analog FTY720 is undergoing clinical trials as an immunomodulatory compound, acting primarily via sphingosine 1-phosphate receptor activation. Sphingolipid and cholesterol homeostasis are closely connected but whether FTY720 affects atherogenesis in humans is not known.
objectiveWe examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages. METHODS AND
resultsFTY720 did not affect cholesterol uptake but inhibited its delivery to the endoplasmic reticulum, reducing cellular free cholesterol cytotoxicity. This was accompanied by increased levels of Niemann-Pick C1 protein (NPC1) and ATP-binding cassette transporter (ABC)A1 proteins and increased efflux of endosomal cholesterol to apolipoprotein A-I. These effects were not dependent on sphingosine 1-phosphate receptor activation. Instead, FTY720 stimulated the production of 27-hydroxycholesterol, an endogenous ligand of the liver X receptor, leading to liver X receptor-induced upregulation of ABCA1. Fluorescently labeled FTY720 was targeted to late endosomes, and the FTY720-induced upregulation of ABCA1 was NPC1-dependent, but the endosomal exit of FTY720 itself was not.
conclusionsWe conclude that FTY720 decreases cholesterol toxicity in primary human macrophages by reducing the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitating its release to physiological extracellular acceptors. Furthermore, FTY720 stimulates 27-hydroxycholesterol production, providing an explanation for the atheroprotective effects and identifying a novel mechanism by which FTY720 modulates signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.