Biology subjects

Miharada, K.

Publications and source records attributed to Miharada, K..

3 recordsLinked to original sources

bioRxiv2023

Maternal sterol 27-hydroxylase is crucial for securing fetal development

The maternal body helps in providing nutrients and degrading toxic metabolites instead of the fetal body; disruptions in these mechanisms affect normal fetal development. Sterol 27-hydroxylase (Cyp27a1) is involved in the alternative pathway of bile acid synthesis, which is enhanced during pregnancy. However, its role in fetal development remains unclear. Here, we demonstrate that maternal Cyp27a1 activity is essential for progression of normal pregnancy and fetal organ formation. Depletion of maternal Cyp27a1 reduced the pregnancy rate and litter size. Newborn mice died of respiratory distress syndrome resulting from the absence of mature alveolar epithelial cells. These phenotypes were caused by 7-hydroxycholesterol (7-HC) accumulating in Cyp27a1-deficient mice. Mechanistically, 7-HC destabilized the Fau protein, mediating ribosome assembly, the downregulation of which caused poor polysome formation, lower protein synthesis, and impaired lung maturation. Overall, this study revealed an essential mechanism of securing fetal development by degrading a toxic metabolite in the maternal body.

developmental biology↗

bioRxiv2023

Metabolic regulation in erythroid differentiation by systemic ketogenesis in fasted mice

Systemic ketogenesis affects murine erythroid differentiation under fasting condition, while less ketone body {beta} OHB boosts fatty acid synthesis and mevalonate pathway along with decreased levels of histone acetylation, which are beneficial for erythroid differentiation and maturation undergoing stressed erythropoiesis. AbstractErythroid terminal differentiation and maturation depends on 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 bone marrow of hepatic Hmgcs2 KO mouse under fasting condition, suggesting that systemic ketogenesis has a profound effect on erythropoiesis. Moreover, we observed significantly activated fatty acids synthesis and mevalonate pathway along with reduced histone acetylation in immature erythrocytes under less systemic ketogenesis condition. Our findings revealed an innovative insight to erythroid differentiation, in which metabolic homeostasis and histone acetylation mediated by ketone bodies are essential factors in adaptation towards nutrient deprivation and stressed erythropoiesis.

cell biology↗

bioRxiv2021

Hepatic Leukemia Factor supports the propagation of leukemia and hematopoietic stem cell function during stress-induced regeneration.

The processes regulating hematopoietic stem cells (HSC) during aging are not fully understood1, but it is clear that the incidence of hematological malignancies increases with age, highlighting the importance of unravelling the cellular and molecular networks involved. Recently, we identified Hepatic Leukemia Factor (HLF) as an essential transcription factor in maintaining the HSC pool during regeneration2 and showed that failure to downregulate HLF leads to disrupted differentiation3. Here, we found that HLF is dispensable for hematopoiesis during systemic aging, but needed during stress-induced hematopoietic recovery of aged HSC after transplantation. Additionally, HLF was dispensable for leukemic initiation but required for disease propagation. Taken together, our findings demonstrate the existence of a HLF-dependent mechanism that uncouples stress-induced regeneration from hematopoietic homeostasis during aging, that can be used by malignant cells to gain stem cell properties to propagate the disease. Key pointsO_LIHLF is dispensable for HSC function and hematopoietic homeostasis during physiological aging, but crucial during stress induced regeneration. C_LIO_LIHLF supports the propagation of leukemia-initiating cells C_LI

cancer biology↗