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While majority of adult hematopoietic stem cells (HSC) are maintained in a dormant state under steady-state conditions, various stress conditions such as myeloablation and infection are known to trigger proliferation and changing lineage output of those cells. However, it is unclear whether and how HSC respond to acute anemic conditions. We found that HSC rapidly expand and differentiate more towards erythroid cells both in vitro and in vivo, upon injection of phenylhydrazine (PHZ) treatment or phlebotomy. Erythropoietin (EPO) has been recognized as a major regulator of erythropoiesis, however, its implication in HSC regulation is not established. In fact, ELISA assay revealed that EPO concentration did not change in the bone marrow (BM) fluid upon PHZ treatment and phlebotomy while the concentration in the peripheral blood significantly increased. Gene expression profiling revealed that expression of lipid metabolism-related genes particularly very low-density lipoprotein receptor (Vldlr) significantly elevated in HSC of PHZ-treated mice. HSC expressing VLDLR at a higher level (VLDLR-high-HSC) generated more erythroid cells in colony forming unit assay. The concentration of a ligand of VLDLR, apolipoprotein E (ApoE), increased in both peripheral blood and BM fluid upon anemia induction. Treatment with recombinant ApoE increased fatty acid oxidation in HSC and increased erythroid production. Contrary, HSC of ApoE knockout (KO) mice didn't observe the enhanced erythroid output upon PHZ injection. ATAC-seq suggested VLDLR-high-HSCs are similar to Erg KO HSC that have lower megakaryopoiesis potential while VLDLR-low-HSCs are similar to platelet-biased vWF+HSCs. These findings suggest that ApoE play a key role in regulating responses of HSC upon acute anemia induction through metabolic and transcriptomic modifications.