3007 – REGULATION OF MEVALONATE PATHWAY IN ERYTHROPOIESIS BY KETOGENESIS IN FASTING MOUSE

Erythroid terminal differentiation and maturation depends on enormous energy supply accompanied by a dramatic metabolic shift. Ketone bodies from the liver are transported into circulation and utilized as crucial fuel for peripheral tissues during periods of fasting. However, the effects of fasting or ketogenesis on hematopoietic stem cells (HSC) and erythroid behavior remain unknown. In our study, we generated a mouse model to investigate the effect of insufficient ketogenesis on erythropoiesis by conditionally knocking out the gene, encoding the liver-specific ketogenic enzyme hydroxymethylglutary-CoA synthase 2 (Hmgcs2 KO). Intriguingly, our results showed that erythroid maturation is enhanced in Hmgcs2 KO (ketone-less) mouse under fasting condition, indicated by an elevated erythrocytes and hemoglobin levels. Metabolite profiling of blood serum showed enriched fatty acid metabolism and cholesterol synthesis in fasting Hmgcs2 KO mice compared to control mice where glycolysis is the main metabolic pathway involved in ad libitum feeding condition. Remarkably, this shows that systemic ketogenesis has a profound effect on erythropoiesis, since Hmgcs2 RNA expression is pretty low in erythrocytes and HSC. Additionally, repeated intermittent fasting induced HSC differentiation bias towards erythroid differentiation in Hmgcs2 KO mice. Transcriptional profiling of these mice showed that the mevalonate pathway in the cytoplasm was highly activated during erythroid differentiation and maturation, while mitochondria membrane potential and ATP contents did not show any significant differences between control and KO mice. Our findings revealed an innovative insight to erythropoiesis, in which fatty acid and cholesterol homeostasis regulated by ketone bodies are essential energy sources in adaptation towards nutrient deficiency or starvation stress.