Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis Journal Article
| Authors: | Murphy, A. J.; Bijl, N.; Yvan-Charvet, L.; Welch, C. B.; Bhagwat, N.; Reheman, A.; Wang, Y.; Shaw, J. A.; Levine, R. L.; Ni, H.; Tall, A. R.; Wang, N. |
| Article Title: | Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis |
| 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. © 2013 Nature America, Inc. All rights reserved. |
| Journal Title: | Nature Medicine |
| Volume: | 19 |
| Issue: | 5 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2013-05-01 |
| Start Page: | 586 |
| End Page: | 594 |
| Language: | English |
| DOI: | 10.1038/nm.3150 |
| PROVIDER: | scopus |
| PUBMED: | 23584088 |
| PMCID: | PMC3683965 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 3 June 2013" - "CODEN: NAMEF" - "Source: Scopus" |
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