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Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis

2013; Nature Portfolio; Volume: 19; Issue: 5 Linguagem: Inglês

10.1038/nm.3150

1546-170X

Andrew Murphy, Nora Bijl, Laurent Yvan‐Charvet, Carrie B. Welch, Neha Bhagwat, Reheman Adili, Yiming Wang, J. Shaw, Ross L. Levine, Heyu Ni, Alan R. Tall, Nan Wang,

Platelet Disorders and Treatments

Nan Wang and colleagues uncover a new function for HDL that may contribute to its anti-atherosclerotic effects. In the bone marrow, HDL removes cholesterol from megakaryocyte progenitor cells in a process requiring the cholesterol transporter ABCG4, thereby dampening megakaryocyte and platelet production. Platelets have a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote atherothrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Here we show that transplantation of bone marrow deficient in ABCG4, a transporter of unknown function, into Ldlr−/− mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. Although not detected in atherosclerotic lesions, Abcg4 was highly expressed in bone marrow megakaryocyte progenitors (MkPs). Abcg4−/− MkPs had defective cholesterol efflux to high-density lipoprotein (HDL), increased cell surface expression of the thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. These consequences of ABCG4 deficiency seemed to reflect disruption of negative feedback regulation of c-MPL signaling by the E3 ligase c-CBL and the cholesterol-sensing LYN kinase. HDL infusion reduced platelet counts in Ldlr−/− mice and in a mouse model of myeloproliferative neoplasm in an ABCG4-dependent fashion. HDL infusions may offer a new approach to reducing atherothrombotic events associated with increased platelet production.