| First Author | Murphy AJ | Year | 2013 |
| Journal | Nat Med | Volume | 19 |
| Issue | 5 | Pages | 586-94 |
| PubMed ID | 23584088 | Mgi Jnum | J:198517 |
| Mgi Id | MGI:5496962 | Doi | 10.1038/nm.3150 |
| Citation | Murphy AJ, et al. (2013) Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med 19(5):586-94 |
| abstractText | 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. |
