Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI.
Mammalian erythrocytes undergo a unique maturation process in which they discard their nuclei and organelles and assume a flexible biconcave shape. We found that altered plasma lipoprotein metabolism can profoundly influence these events. Abnormal erythrocyte morphology was observed in hypercholesterolemic mice lacking the high-density lipoprotein receptor SR-BI. This was exacerbated by feeding mice a high-cholesterol diet or, more dramatically, by inactivating the apolipoprotein E gene. Erythrocytes from SR-BI(-/-)/apolipoprotein E(-/-) mice and SR-BI(-/-) mice that were fed cholesterol had markedly increased membrane cholesterol. Their morphology appeared immature, with macrocytosis, irregular shape, and large autophagolysosomes. Autophagolysosomes from SR-BI(-/-)/apolipoprotein E(-/-) erythrocytes were expelled when the erythrocytes were transfused into wild-type animals or incubated in vitro with normolipidemic serum or the cholesterol-sequestering agent methyl cyclodextrin. We propose that autophagocytosis and phagolysosome expulsion are essential steps in erythroid maturation and that expulsion is inhibited in the presence of markedly increased cellular cholesterol.
Holm
Teresa M
TM
Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.
Braun
Anne
A
Trigatti
Bernardo L
BL
Brugnara
Carlo
C
Sakamoto
Masa
M
Krieger
Monty
M
Andrews
Nancy C
NC
D000740:Anemia / Q000097:blood / Q000139:chemically induced / Q000209:etiology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002784:Cholesterol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000502:physiology; D004912:Erythrocytes / Q000473:pathology* / Q000648:ultrastructure; D004920:Erythropoiesis / Q000187:drug effects* / Q000235:genetics; D006937:Hypercholesterolemia / Q000097:blood; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000502:physiology; D051116:Receptors, Scavenger; D012156:Reticulocytes / Q000473:pathology / Q000648:ultrastructure; D051122:Scavenger Receptors, Class B
D001057:Apolipoproteins E; D018955:CD36 Antigens; D002352:Carrier Proteins; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein; D002784:Cholesterol