title: Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children.
abstract: Previous studies have shown that mice with defects in cellular cholesterol efflux show hematopoietic stem cell (HSPC) and myeloid proliferation, contributing to atherogenesis. We hypothesized that the combination of hypercholesterolemia and defective cholesterol efflux would promote HSPC expansion and leukocytosis more prominently than either alone. We crossed Ldlr(-/-) with Apoa1(-/-) mice and found that compared to Ldlr(-/-) mice, Ldlr(-/-)/Apoa1(+/-) mice, with similar LDL-cholesterol levels but reduced HDL-cholesterol (HDL-C) levels, had expansion of HSPCs, monocytosis and neutrophilia. Ex vivo studies showed that HSPCs expressed high levels of Ldlr, Scarb1 (Srb1), and Lrp1 and were able to take up both native and oxidized LDL. Native LDL directly stimulated HSPC proliferation, while co-incubation with reconstituted HDL attenuated this effect. We also assessed the impact of HDL-C levels on monocytes in children with familial hypercholesterolemia (FH) (n = 49) and found that subjects with the lowest level of HDL-C, had increased monocyte counts compared to the mid and higher HDL-C levels. Overall, HDL-C was inversely correlated with the monocyte count. These data suggest that in mice, a balance of cholesterol uptake and efflux mechanisms may be one factor in driving HSPC proliferation and monocytosis. Higher monocyte counts in children with FH and low HDL-cholesterol suggest a similar pattern in humans.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA. st2367@columbia.edu
authors.forename: Sonia
authors.initials: S
authors.lastname: Tolani
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Pagler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Bochem
authors.forename: Sandra
authors.initials: S
authors.lastname: Abramowicz
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.forename: Prabhakara R
authors.initials: PR
authors.lastname: Nagareddy
authors.forename: Steve
authors.initials: S
authors.lastname: Holleran
authors.forename: G K
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D000293:Adolescent; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D008076:Cholesterol, HDL / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein