Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia.
نویسندگان
چکیده
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.
منابع مشابه
Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management
Sitosterolemia is an autosomal recessive disorder characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, severe hypercholesterolemia have been reported in patients with sitosterolemia, especially in children. Sitosterolemia is caused by increased intestinal absorption and decreased ...
متن کاملPlatelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia.
Sitosterolemia is a rare, autosomal recessive disease caused by mutations in the adenosine triphosphate-binding cassette transporter genes ABCG5 or ABCG8 that result in accumulation of xenosterols in the body. Clinical manifestations include tendon xanthomas, premature coronary artery disease, hemolytic anemia, macrothrombocytopenia, and bleeding. Although the effect of sterol accumulation on t...
متن کاملSitosterolemia: platelets on high-sterol diet.
S itosterolemia is a rare inherited lipid metabolic disorder characterized by the presence of xanthomas, premature coronary artery disease, and atherosclerotic disease. The hallmark of sitosterolemia is diagnostically elevated plasma levels of dietary plant sterols (eg, sitosterol), which is found in high concentrations in olives, avocados, and pecan nuts. Sitosterolemia is caused by mutations ...
متن کاملPlatelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of Sitosterolemia Running head: Phytosterols affect platelet structure/function
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226 Dept. of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226 Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI 53226 Clement J. Zablocki Veterans Affairs Medical Center, Division of Endocrinology, Metabolism, and Clinical Nutrition, Pharmacology and Cellular Biology The Cardiovascular ...
متن کاملEzetimibe effectively reduces plasma plant sterols in patients with sitosterolemia.
BACKGROUND Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops. METHODS AND RESULTS In this multicenter,...
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ورودعنوان ژورنال:
- The Journal of biological chemistry
دوره 283 10 شماره
صفحات -
تاریخ انتشار 2008