title: miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux.
abstract: Cholesterol homeostasis is fundamental to human health and is, thus, tightly regulated. MicroRNAs exert potent effects on biological pathways, including cholesterol metabolism, by repressing genes with related functions. We reasoned that this mode of pathway regulation could be exploited to identify novel genes involved in cholesterol homeostasis.
  
  
  
  Here, we identify oxysterol-binding protein-like 6 (OSBPL6) as a novel target of 2 miRNA hubs regulating cholesterol homeostasis: miR-33 and miR-27b. Characterization of OSBPL6 revealed that it is transcriptionally regulated in macrophages and hepatocytes by liver X receptor and in response to cholesterol loading and in mice and nonhuman primates by Western diet feeding. OSBPL6 encodes the OSBPL-related protein 6 (ORP6), which contains dual membrane- and endoplasmic reticulum-targeting motifs. Subcellular localization studies showed that ORP6 is associated with the endolysosomal network and endoplasmic reticulum, suggesting a role for ORP6 in cholesterol trafficking between these compartments. Accordingly, knockdown of OSBPL6 results in aberrant clustering of endosomes and promotes the accumulation of free cholesterol in these structures, resulting in reduced cholesterol esterification at the endoplasmic reticulum. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. Moreover, we show that hepatic expression of OSBPL6 is positively correlated with plasma levels of high-density lipoprotein cholesterol in a cohort of 200 healthy individuals, whereas its expression is reduced in human atherosclerotic plaques.
  
  
  
  These studies identify ORP6 as a novel regulator of cholesterol trafficking that is part of the miR-33 and miR-27b target gene networks that contribute to the maintenance of cholesterol homeostasis.
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ouimet
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hennessy
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Coen
authors.initials: C
authors.lastname: van Solingen
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Koelwyn
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016.
authors.forename: Maryem A
authors.initials: MA
authors.lastname: Hussein
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.affiliation: University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
authors.affiliation: Saha Cardiovascular Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Perisic
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.affiliation: Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.affiliation: Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
mesh_terms: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites; D001692:Biological Transport; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D011485:Protein Binding; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000098825:Oxysterol Binding Proteins
chemical_list: D020413:3' Untranslated Regions; C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D008076:Cholesterol, HDL; D000071518:Liver X Receptors; C531388:MIRN27 microRNA, human; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; C550417:Mirn33 microRNA, mouse; D011973:Receptors, LDL; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D002784:Cholesterol
keywords: cholesterol; cholesterol homeostasis; lipids and lipoproteins; macrophages; microRNA