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.
authors.affiliation: Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Nora
authors.initials: N
authors.lastname: Bijl
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
authors.forename: Carrie B
authors.initials: CB
authors.lastname: Welch
authors.forename: Neha
authors.initials: N
authors.lastname: Bhagwat
authors.forename: Adili
authors.initials: A
authors.lastname: Reheman
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
authors.forename: James A
authors.initials: JA
authors.lastname: Shaw
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
mesh_terms: D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D013922:Thrombocytosis / Q000378:metabolism*; D013927:Thrombosis / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters; C486685:Abcg4 protein, mouse; C481270:Mpl protein, mouse; D011973:Receptors, LDL; D053628:Receptors, Thrombopoietin; D002784:Cholesterol; D044767:Ubiquitin-Protein Ligases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases