title: Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia.
abstract: Mutations in either ABCG5 or ABCG8 cause sitosterolemia, an inborn error of metabolism characterized by high plasma plant sterol concentrations. Recently, macrothrombocytopenia was described in a number of sitosterolemia patients, linking hematological dysfunction to disturbed sterol metabolism. Here, we demonstrate that macrothrombocytopenia is an intrinsic feature of murine sitosterolemia. Abcg5-deficient (Abcg5(-/-)) mice showed a 68% reduction in platelet count, and platelets were enlarged compared with wild-type controls. Macrothrombocytopenia was not due to decreased numbers of megakaryocytes or their progenitors, but defective megakaryocyte development with deterioration of the demarcation membrane system was evident. Lethally irradiated wild-type mice transplanted with bone marrow from Abcg5(-/-) mice displayed normal platelets, whereas Abcg5(-/-) mice transplanted with wild-type bone marrow still showed macrothrombocytopenia. Treatment with the sterol absorption inhibitor ezetimibe rapidly reversed macrothrombocytopenia in Abcg5(-/-) mice concomitant with a strong decrease in plasma plant sterols. Thus, accumulation of plant sterols is responsible for development of macrothrombocytopenia in sitosterolemia, and blocking intestinal plant sterol absorption provides an effective means of treatment.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Janine K
authors.initials: JK
authors.lastname: Kruit
authors.forename: A Lyndsay
authors.initials: AL
authors.lastname: Drayer
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Nel
authors.initials: N
authors.lastname: Blom
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Olthof
authors.forename: Pieter J J
authors.initials: PJ
authors.lastname: Sauer
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D048429:Cell Size; D004195:Disease Models, Animal; D007408:Intestinal Absorption / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010976:Platelet Count; D012855:Sitosterols / Q000378:metabolism*; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D012855:Sitosterols