Kruit Janine K, Drayer A Lyndsay, Bloks Vincent W, Blom Nel, Olthof Sandra G, Sauer Pieter J J, de Haan Gerald, Kema Ido P, Vellenga Edo, Kuipers Folkert
Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Centre Groningen, Groningen, The Netherlands.
J Biol Chem. 2008 Mar 7;283(10):6281-7. doi: 10.1074/jbc.M706689200. Epub 2007 Dec 21.
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.
ABCG5或ABCG8基因的突变会导致谷甾醇血症，这是一种先天性代谢紊乱疾病，其特征是血浆植物甾醇浓度升高。最近，在一些谷甾醇血症患者中发现了大血小板减少症，这将血液学功能障碍与紊乱的甾醇代谢联系了起来。在此，我们证明大血小板减少症是小鼠谷甾醇血症的一个内在特征。Abcg5基因缺陷（Abcg5(-/-)）小鼠的血小板计数降低了68%，并且与野生型对照相比，血小板体积增大。大血小板减少症并非由于巨核细胞或其祖细胞数量减少所致，而是明显存在巨核细胞发育缺陷以及分界膜系统的退化。接受来自Abcg5(-/-)小鼠骨髓移植的经致死剂量照射的野生型小鼠血小板正常，而接受野生型骨髓移植的Abcg5(-/-)小鼠仍表现出大血小板减少症。使用甾醇吸收抑制剂依泽替米贝进行治疗可迅速逆转Abcg5(-/-)小鼠的大血小板减少症，同时血浆植物甾醇显著降低。因此，植物甾醇的蓄积是谷甾醇血症中大血小板减少症发生的原因，而阻断肠道植物甾醇吸收提供了一种有效的治疗手段。
