Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis

Platelets play a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote athero-thrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Transplantation of bone marrow (BM) deficient in ABCG4, a transporter of unknown function, into Ldlr(−/−) mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. While not detected in lesions, Abcg4 was highly expressed in BM megakaryocyte progenitors (MkP). Abcg4(−/−) MkPs displayed defective cholesterol efflux to HDL, increased cell surface levels of thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. This appeared to reflect disruption of the negative feedback regulation of c-MPL levels and signaling by E3 ligase c-CBL and cholesterol-sensing LYN kinase. HDL infusions reduced platelet counts in Ldlr(−/−) mice and in a mouse model of myeloproliferative neoplasm, in a completely ABCG4-dependent fashion. HDL infusions may offer a novel approach to reducing athero-thrombotic events associated with increased platelet production.