Abstract 436: Hypercholesterolemia Impairs Erythropoiesis in an Intrinsic Scavenger Receptor BI Deficiency-dependent Manner

Abstract

Scavenger receptor BI (SR-BI) is an HDL receptor. SR-BI^-/- mice display abnormal erythropoiesis as indicated by reticulocytosis, accumulation of erythroid cells in spleen and blockage of erythroblast development. Previous studies proposed that hypercholesterolemia induced by SR-BI deficiency led to the abnormal erythropoiesis in SR-BI^-/- mice. However, the expression of SR-BI on erythroid cells leaves us to ask what the role of intrinsic SR-BI in erythropoiesis is. In this study, we utilized three independent animal models to assess the hypothesis that intrinsic SR-BI is required for erythropoiesis and its deficiency is permissive for hypercholesterolemia to impact erythropoiesis.

First, in an LDLR knockout model, we found that SR-BI^+/+ LDLR^-/- mice had high cholesterol concentrations similar to SR-BI^-/-LDLR^+/+ mice, but had normal erythropoiesis. In contrast, SR-BI^-/- LDLR^-/- mice had a 2.2-fold increase in reticulocyte percentage, 40% increase in spleen erythroid cells, and a significant increase in the early-to-late erythroblast ratio compared with SR-BI^-/- LDLR^+/+ mice, suggesting that hypercholesterolemia can exacerbate the abnormal erythropoiesis only in the absence of SR-BI. Secondly, in a liver specific SR-BI deficiency model (SR-BI I179N mutant mice), we found that a 90% decrease in liver SR-BI expression in the mutant mice resulted in a 70% increase in plasma cholesterol concentrations, but did not induce reticulocytosis or spleen erythroid cell accumulation, implying the existence of other factor rather than SR-BI deficiency-induced hypercholesterolemia. Finally, in a bone marrow transplantation model, we found that compared with those received SR-BI^+/+ BMCs, SR-BI^+/+ mice receiving SR-BI^-/- BMCs had a more than 2-fold increase in reticulocyte percentage, 32% increase in spleen erythroid cells, and a more than 5-fold increase in early-to-late erythroblast ratio. Conversely, SR-BI^+/+ BMCs injection decreased the percentage and number of erythroid cells in spleen and the early-to-late erythroblast ratio in SR-BI^-/- mice.

In conclusion, our data demonstrated that intrinsic SR-BI is required for erythropoiesis and hypercholesterolemia impairs erythropoiesis in an intrinsic SR-BI deficiency-dependent manner.