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J. Biol. Chem., Vol. 283, Issue 10, 6281-6287, March 7, 2008

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Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia^*

Janine K. Kruit¹, A. Lyndsay Drayer, Vincent W. Bloks, Nel Blom^¶||, Sandra G. Olthof^||, Pieter J. J. Sauer, Gerald de Haan^**, Ido P. Kema, Edo Vellenga^||, and Folkert Kuipers²

From the Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands, the Sanquin Blood Bank, North East Region, 9713 GZ Groningen, The Netherlands, the ^¶Department of Cell Biology, Section of Electron Microscopy, the Departments of ^||Hematology and ^**Cell Biology, Section of Stem Cell Biology, and the Department of Pathology and Laboratory Medicine, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

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.

Received for publication, August 13, 2007 , and in revised form, November 29, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Tables 1 and 2.

¹ Supported by Netherlands Heart Foundation Grant 2001B043. Present address: Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.

² To whom correspondence should be addressed. Tel.: 31-503-632-669; Fax: 31-503-611-746; E-mail: f.kuipers{at}med.umcg.nl.

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