July 19 2019
The "D5 Medical & Life Science Seminar" course will be offered by International Research Center for Medical Sciences (IRCMS). It will run from April 2019 to March 2020, with lectures given by scientists who are affiliated with IRCMS or in collaboration with researchers at IRCMS. The lectures will be given once a month, in English, and by leading scientists in the relevant research field. Students will be taught: 1) how normal physiological functions are maintained in the human body; 2) how abnormalities in these systems (e.g., cancer) are studied using experimental models; 3) cutting-edge technologies (including single cell level imaging and omics analysis) used for mechanistic understanding of these abnormalities; 4) efforts and progresses in finding cure for human diseases associated with these abnormalities; and 5) importance of understanding disease mechanisms using cross-disciplinary approaches.
Date : August 28, 2019 (Wednesday)
Time : 17:30 -
Venue : IRCMS 1F Meeting Lounge
Speaker : Yuichiro Arima M.D., Ph.D.
. Assistant Professor, Faculty of Life Sciences,
Kumamoto University, Japan
Title : Ketone Body Metabolism in Health and Diseases
Ketone body metabolism functions as an emergent energy server in the starved condition. Recent findings illuminated beneficial roles of ketone bodies for health and disease. However, physiological roles of ketogenesis are not fully elucidated. We characterised ketogenesis by measuring the concentration of beta-hydroxybutyrate (3OHB) and found that 3OHB concentration in neonates was significantly elevated in the free-feeding condition compared to adult mice.
To address the role of neonatal ketogenesis, we newly generated the murine model of insufficient ketogenesis. We targeted HMG-CoA synthase 2 (Hmgcs2), rate-limiting enzymes for ketogenesis, and CRISPR/Cas9 system allowed to establish two lines of Hmgcs2 deletion mutants. Hmgcs2 homozygous mutant (Hmgcs2 KO). Hmgcs2 KO mice could not produce hmgcs2 protein and the concentration of ketone bodies were significantly low.
We could not find apparent abnormalities at birth, however, microvesicular hepatosteatosis rapidly progressed in hmgcs2 KO neonates. Metabolome analysis revealed decreased energy production in spite of the significant accumulation of acetyl-CoA in KO liver. Section electron microscope revealed KO neonates held many damaged mitochondria and oxygen consumption rate was significantly decreased in hmgcs2 KO hepatocytes. We also found enhanced acetylation of mitochondrial proteins in KO liver.
These data represented that neonatal ketogenesis buffered Acetyl-CoA accumulation and kept the metabolic homeostasis. Furthermore, we also observed hyperacetylation of mitochondrial protein in adult murine hearts, which held heart failure with preserved ejection fraction (HFpEF). In this session, we will introduce our works, related to ketogenesis, post-translational modifications and HFpEF.