RED CELLS 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 highcholesterol diet or, more dramatically, by inactivating the apolipoprotein E gene. Erythrocytes from SR-BI2/2/apolipoprotein E2/2 mice and SR-BI2/2 mice that were fed cholesterol had markedly increased membrane cholesterol. Their morphology appeared immature, with macrocytosis, irregular shape, and large autophagolysosomes. Autophagolysosomes from SR-BI2/2/apolipoprotein E2/2 erythrocytes were expelled when the erythrocytes were transfused into wildtype animals or incubated in vitro with normolipidemic serum or the cholesterolsequestering 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. (Blood. 2002;99:1817-1824)