Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis Academic Article uri icon

abstract

  • 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.

authors

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

publication date

  • April 14, 2013

has subject area