GW24-e0058 Effects of SR-BI Deficiency and Hypercholesterolemia on Erythropoiesis

Objectives Scavenger receptor BI (SR-BI) is a key regulator of high density lipoprotein (HDL) metabolism. Recent studies showed that mice deficient in SR-BI exhibit impaired erythropoiesis and it has been proposed that the high cholesterol environment plays a major role in the abnormal erythropoiesis. In this study, we observed the effect of SR-BI deficiency and hypercholesterolemia on erythropoiesis. Methods Three animal models were utilised to evaluate the role of SR-BI and hypercholesterolemia in erythropoiesis. 1. First, we used a high fat diet-induced hypercholesterolemia model. High fat diet caused a 2-fold increase in plasma cholesterol levels in SR-BI+/+ (170 mg/dl to 352 mg/dl) and SR-BI-/- mice (315 mg/dl to 718 mg/dl). 2. Then, we used SR-BI/LDLR double knockout mice to further elucidate the contribution of hypercholesterolemia to erythropoiesis. 3. Finally, we investigated the contribution of hepatic SR-BI using ScarbII179N mutant mice, whose hepatic SR-BI expression has been knocked down by 90% and therefore has a 1.7-fold increase in plasma cholesterol levels compared to wild type controls. Results The high fat diet treatment markedly exacerbated the impaired erythropoiesis in SR-BI-/- mice as shown by 4-fold increase in reticulocyte percentage and 2.5-fold increase in early-to-late erythroblast ratio. Unexpectedly, high fat feeding did not induce abnormal erythropoiesis in SR-BI+/+ mice despite of hypercholesterolemia in these mice. SR-BI/LDLR double knockout mice had 2-fold increase in plasma cholesterol levels and exhibited severer impaired erythropoiesis, similar to high fat-fed SR-BI-/- mice. Interestingly, despite of hyperlipidemia, LDLR single knockout mice did not display impaired erythropoiesis. ScarbII179N mice displayed normal erythropoiesis, similar to wild type controls. These findings indicate that hypercholesterolemia does not cause abnormal erythropoiesis in the presence of SR-BI, but markedly impairs erythropoiesis in the absence of SR-BI. Conclusions Our study suggest that SR-BI is essential for normal erythropoiesis, and that hypercholesterolemia and SR-BI deficiency synergistically exacerbated impaired erythropoiesis.