title: Orp8 deficiency in bone marrow-derived cells reduces atherosclerotic lesion progression in LDL receptor knockout mice.
abstract: BACKGROUND
  Oxysterol binding protein Related Proteins (ORPs) mediate intracellular lipid transport and homeostatic regulation. ORP8 downregulates ABCA1 expression in macrophages and cellular cholesterol efflux to apolipoprotein A-I. In line, ORP8 knockout mice display increased amounts of HDL cholesterol in blood. However, the role of macrophage ORP8 in atherosclerotic lesion development is unknown.
  
  
  RESULTS
  LDL receptor knockout (KO) mice were transplanted with bone marrow (BM) from ORP8 KO mice and C57Bl/6 wild type mice. Subsequently, the animals were challenged with a high fat/high cholesterol Western-type diet to induce atherosclerosis. After 9 weeks of Western-Type diet feeding, serum levels of VLDL cholesterol were increased by 50% in ORP8 KO BM recipients compared to the wild-type recipients. However, no differences were observed in HDL cholesterol. Despite the increase in VLDL cholesterol, lesions in mice transplanted with ORP8 KO bone marrow were 20% smaller compared to WT transplanted controls. In addition, ORP8 KO transplanted mice displayed a modest increase in the percentage of macrophages in the lesion as compared to the wild-type transplanted group. ORP8 deficient macrophages displayed decreased production of pro-inflammatory factors IL-6 and TNFα, decreased expression of differentiation markers and showed a reduced capacity to form foam cells in the peritoneal cavity.
  
  
  CONCLUSIONS
  Deletion of ORP8 in bone marrow-derived cells, including macrophages, reduces lesion progression after 9 weeks of WTD challenge, despite increased amounts of circulating pro-atherogenic VLDL. Reduced macrophage foam cell formation and lower macrophage inflammatory potential are plausible mechanisms contributing to the observed reduction in atherosclerosis.
authors.affiliation: Div. of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: van Kampen
authors.affiliation: Dept. of Lipid Signalling and Homeostasis, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Beaslas
authors.affiliation: Div. of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Reeni B
authors.initials: RB
authors.lastname: Hildebrand
authors.affiliation: Div. of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Lammers
authors.affiliation: Div. of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.affiliation: Dept. of Lipid Signalling and Homeostasis, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.affiliation: Div. of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000473:pathology; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D007958:Leukocyte Count; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009151:Mustard Gas; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D011987:Receptors, Steroid / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D000098825:Oxysterol Binding Proteins; D000097382:CD68 Molecule
chemical_list: D064286:ATP Binding Cassette Transporter 1; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D002784:Cholesterol; D016207:Cytokines; D018836:Inflammation Mediators; D009151:Mustard Gas; D011973:Receptors, LDL; D011987:Receptors, Steroid; D014280:Triglycerides; D000098825:Oxysterol Binding Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule