title: FTY720 stimulates 27-hydroxycholesterol production and confers atheroprotective effects in human primary macrophages.
abstract: BACKGROUND
  The 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.
  
  
  OBJECTIVE
  We examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages.
  
  
  RESULTS
  FTY720 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Institute of Biomedicine/Anatomy, Haartmaninkatu 8, University of Helsinki, Finland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Blom
authors.forename: Nils
authors.initials: N
authors.lastname: Bäck
authors.forename: Aino-Liisa
authors.initials: AL
authors.lastname: Mutka
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Zaiguo
authors.initials: Z
authors.lastname: Li
authors.forename: Angel
authors.initials: A
authors.lastname: de Lera
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D018929:Cell Culture Techniques; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D051116:Receptors, Scavenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D002352:Carrier Proteins; D002788:Cholesterol Esters; D006888:Hydroxycholesterols; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D057093:Orphan Nuclear Receptors; D011409:Propylene Glycols; D051116:Receptors, Scavenger; C032629:acetyl-LDL; C076996:27-hydroxycholesterol; D002784:Cholesterol; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine