Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Janine K Kruit,A Lyndsay Drayer,Vincent W Bloks,Nel Blom,Sandra G Olthof,Pieter J.J Sauer,Gerald De Haan,Ido P Kema,Edo Vellenga,Folkert Kuipers

doi:10.1074/jbc.m706689200

Janine K Kruit, A Lyndsay Drayer + Show 8 more

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https://doi.org/10.1074/jbc.m706689200

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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.

Highlights

IntroductionPlant sterols structurally differ from cholesterol only by the presence of an additional methyl or ethyl group at C-24 (campesterol and sitosterol, respectively), in some cases with an additional double bond at C-22 (brassicasterol and stigmasterol, respectively)
Plant sterols structurally differ from cholesterol only by the presence of an additional methyl or ethyl group at C-24, in some cases with an additional double bond at C-22
Using an established mouse model of sitosterolemia [18], we have shown that high levels of dietary plant sterols have profound and deleterious effects on platelet formation

Summary

Introduction

Plant sterols structurally differ from cholesterol only by the presence of an additional methyl or ethyl group at C-24 (campesterol and sitosterol, respectively), in some cases with an additional double bond at C-22 (brassicasterol and stigmasterol, respectively). Mice lacking Abcg show high levels of dietary plant sterols that appear to be associated with defective megakaryocyte development and disturbed formation of the demarcation membrane system, probably underlying defective platelet formation Macrothrombocytopenia in these mice could not be cured by transplantation of wild-type bone marrow but was rapidly reversed upon decreasing plasma plant sterol levels by treatment with ezetimibe, a clinically used intestinal sterol absorption inhibitor. These data clearly establish that plant sterols, when present in high concentrations, have profound and deleterious effects on platelet biology and on blood coagulation

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