Sitosterolemia: 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 in 2 genes, ABCG5 and ABCG8, tandemly located in a head-to-head orientation on chromosome 2p21. ABCG5 and ABCG8 encode adenosine triphosphate–binding cassette transporters, ABCG5 and ABCG8 (also called sterolin-1 and -2, respectively), which are expressed at the highest levels in hepatocytes and enterocytes in humans and mice. Deficiency in ABCG5 or ABCG8 cause increased sterol intestinal absorption and decreased biliary excretion, and levels of Abcg5 and Abcg8 mRNAs increase in mice within 1 week of beginning a high-cholesterol diet. Thus, ABCG5 and ABCG8 form a functional heterodimer that needs to be expressed coordinately and mediates efflux of dietary sterol from the small intestine, thus protecting humans from sterol accumulation. Mediterranean stomatocytosis/ macrothrombocytopenia has been identified as the hematological presentation of sitosterolemia. The disorder is characterized by stomatocytic hemolysis, large platelets, splenomegaly, and bleeding. Consistently, mice genetically modified to lack Abcg5, and “thrombocytopenia and cardiomyopathy” (trac) mice presenting a natural nonsense mutation W462X in Abcg5, have severe macrothrombocytopenia and strong bleeding tendency. Both Abcg5 and Abcg5 mice have splenomegaly and increased counts of megakaryocyte progenitors in their bone marrow and spleen. Megakaryocyte development is defective in both mouse models, with perturbation of the normally highly invaginated demarcation membrane system that is crucial for platelet formation. Hematological parameters are normalized when bone marrow cells from Abcg5 mice are transplanted into irradiated wild-type mice or when Abcg5 mice are treated with the clinically used intestinal sterol absorption inhibitor ezetimibe. Serum from Abcg5 mice also inhibits proplatelet formation by wild-type fetal liver–derived megakaryocytes. Thus, the macrothrombocytopenia associated with Abcg5 deficiency is caused by increased plasma plant sterol levels resulting from defective ABCG5/ABCG8 heterodimer function in the liver and small intestine, and not to intrinsic megakaryocyte defects. The mouse models differ in the severity of the hemolytic anemia because red blood cell counts and their resistance to hemolytic stress are only mildly affected in Abcg5 mice, whereas Abcg5 mice have a mild hemolytic anemia with increased reticulocyte numbers. The differences are likely due to strain background and/or diet effects. Kanaji et al address the concerns of the previous studies and further decipher the cellular mechanisms responsible for the bleeding abnormality and macrothrombocytopenia in 2 mouse models of sitosterolemia. Abcg5 and Abcg8 mice were backcrossed to Impaired ABCG5/ABCG8 heterodimer function in Abcg5 /2 or Abcg8 /2 hepatocytes and enterocytes leads to increased plasma sterol levels. Sterols accumulate in the platelet membrane, resulting in calpain activation, reduced aIIbb3 surface expression, loss of the GPIba-FlnA linkage, microparticle formation, and poor hemostatic functions.