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-Bl. This was exacerbated by feeding mice a high-cholesterol diet or, more dramatically, by Inactivating the apolipoproteln E gene. Erythrocytes from SR-B1(-/-)/apollpoprotein E-/- mice and SR-B1(-/-) mice that were fed cholesterol had markedly increased membrane cholesterol. Their morphology appeared Immature, with macrocytosis, irregular shape, and large autophagolysosomes. Autophagolysosomes from SR-B1(-/-)/apolipoprotein E-/- erythrocytes were expelled when the erythrocytes were transfused into wildtype 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.