【Publications】Metabolic regulation in erythroid differentiation by systemic ketogenesis in fasted mice

January 26 2024

Lab: Toshio Suda

Paper information

Tile:

Metabolic regulation in erythroid differentiation by systemic ketogenesis in fasted mice

Wenjuan Ma, Yuichiro Arima, Terumasa Umemoto, Tomomasa Yokomizo, Yuqing Xu, Kenichi Miharada, Yosuke Tanaka, and Toshio Suda* (*Corresponding author)

Experimental Hematology  2023/10/16  129  1-13 (January 2024) DOI: 10.1016/j.exphem.2023.10.003

Highlights

• Fasting drives erythropoiesis, which is negatively related to ketone body levels

• Activated fatty acid and cholesterol synthesis enhance erythroid differentiation

• Inhibition of histone deacetylase by β-hydroxybutyrate affects erythroid differentiation at an early stage

Abstract:

Erythroid terminal differentiation and maturation depend on an enormous energy supply. During periods of fasting, ketone bodies from the liver are transported into circulation and utilized as crucial fuel for peripheral tissues. However, the effects of fasting or ketogenesis on erythroid behavior remain unknown. Here, we generated a mouse model with insufficient ketogenesis by conditionally knocking out the gene encoding the hepatocyte-specific ketogenic enzyme hydroxymethylglutary-CoA synthase 2 (Hmgcs2 KO). Intriguingly, erythroid maturation was enhanced with boosted fatty acid synthesis in the bone marrow of a hepatic Hmgcs2 KO mouse under fasting conditions, suggesting that systemic ketogenesis has a profound effect on erythropoiesis. Moreover, we observed significantly activated fatty acid synthesis and mevalonate pathways along with reduced histone acetylation in immature erythrocytes under a less systemic ketogenesis condition. Our findings revealed a new insight into erythroid differentiation, in which metabolic homeostasis and histone acetylation mediated by ketone bodies are essential factors in adaptation toward nutrient deprivation and stressed erythropoiesis.