Yuichiro Arima
M.D., Ph.D.
Associate Professor (Vice Director)


  We have two important themes: the relationship between cardiovascular development and diseases, and ketone body metabolism. In addition, we value seeing the morphology precisely, and we are trying to create a new imaging technique using the computed tomography (CT).


1. Association between cardiovascular development and adult-onset diseases

    Developmental Origins of Health and Diseases (DOHaD) is known as the concept that the perinatal environment influences disease predisposition trait in adult (susceptible trait to lifestyle-related diseases). In particular, many reports have been published on low birth weight infants, and epidemiologically, it has been clarified that the risk of developing hypertension and ischemic heart disease after adulthood increases with low birth weight. However, it is still unclear why perinatal stress increases the risk of heart disease in the future, and sufficient measures cannot be taken.

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   Therefore, in order to verify the DOHaD theory by basic research, our laboratory is conducting analyzes to clarify the effects on the pathogenesis of heart disease by making full use of various mouse models. By advancing this project, we aim to build a long-lived society where even those who have experienced difficulties in the perinatal period can live healthy and prosperous lives.


2. Effects of ketone bodies on health and diseases

         Ketone bodies are metabolites, which rise during fasting. They are known as an energy source during starvation. In the process of analyzing the relationship between heart development and pathology in theme 1, I happened to notice that ketone body synthesis becomes active during the neonatal period. To elucidate the significance of ketone body metabolism in the neonatal period, we generated knockout mice for HMG-CoA synthase2 (Hmgcs2), the rate-limiting enzyme for ketone body synthesis. Analysis of Hmgcs2 KO neonates revealed that it rapidly develops fatty liver after birth. It was also found that in insufficient ketone body production, hyper-acetylation of mitochondrial proteins suppress their function(Arima Nature Metabolism 2021).

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         Fortunately, I had the opportunity to discover a new function of ketone body metabolism, but at the same time, various questions and interests arose. Until now, the accumulation of ketone bodies has led to a serious condition called ketoacidosis, so the negative effects have been emphasized. However, recent reports illuminate that moderate increase on ketone bodies have the beneficial role for health. But it is very difficult to define this "moderate" ketone body concentration for health. Therefore, we are also trying to develop a murine model that can artificially control ketone body metabolism by applying optical engineering techniques.

3. Analysis of micro-architecture using X-ray CT

           Computed tomography (CT) is a non-destructive imaging method and an indispensable tool for diagnosing and treating diseases. The spatial resolution of CT used clinically is about 0.5 mm, but the technological innovation of CT equipment used in the research field is remarkable, and the highest performance CT equipment is capable of spatial discrimination of 500 nm. The Faculty of Engineering at Kumamoto University has created an organization called the X-Earth Center that integrates these latest CT devices, and we participate in this group to establish the collaborative research between medicine and engineering.

         We have developed tissue specific CT imaging methods, such as the structure of murine blood vessels (Arima JAHA 2018, Seya JoVE 2021). Using these methodological advances, we try to develop a new quantitative analysis for microenvironmental structures.

X-Earth center:

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有馬研究室では、心血管の発生と病態との関連、そしてケトン体代謝の二つを重要なテーマとして研究しています。また、nano X線CTや共焦点顕微鏡などのイメージング技術を駆使することで、形態を見ることを大切にしています。


1. 心血管の発生と病態との関連

 生活習慣病胎児発症起源説(Developmental Origins of Health and Diseases; DOHaD "ドーハッド"と呼びます)という学説があります。この学説は、胎生期や生後早期の周産期発育環境が、成人後の疾病素因形成(生活習慣病になりやすい体質の形成)に影響するという概念です。特に、低出生体重児について多くの報告が発表され、疫学的には低出生体重時では成人後の高血圧・虚血性心疾患発症リスクが上昇することが明らかとなっています。日本では現在10人に1人のお子様が低出生体重児として生まれていて、看過することのできないリスクです。しかしながら、周産期にストレスが加わると将来の心疾患リスクが上昇する理由は未だ不明であり、充分な対策を講じることができません。





2.  ケトン体が生体に及ぼす影響

 ケトン体は空腹時に上昇する代謝産物で、飢餓時のエネルギー源として知られています。私はテーマ1の心臓発生と病態との関連を解析する過程で、偶然にも新生児期にケトン体合成が活発になることに気づき、ケトン体代謝に興味を持ちました。新生仔期のケトン体代謝の意義を明らかにするため、ケトン体合成の律速段階酵素であるHMG-CoA synthase2(Hmgcs2)のノックアウトマウスを作成しました。このケトン体合成不全マウスを解析したところ、生後急速に脂肪肝になることがわかり、ケトン体合成不全では、ミトコンドリア内にケトン体の原料となるアセチルCoAが過剰に蓄積し、ミトコンドリアタンパクに過剰なアセチル化修飾を加える結果、機能を阻害することがわかりました(Arima Nature Metabolism 2021)。







3. X線CTを用いた微細構造の解析

Computed Tomography (CT)は非破壊的に内部構造を評価できる画層撮影法で、病気の診断や治療に用いられる欠かせないツールです。臨床で利用されるCTの空間分解能は約0.5mm程度ですが、研究領域で利用されるCT装置の技術革新はめざましく、最高性能のCT装置では500nmの空間識別が可能となっています。熊本大学工学部では、それら最新のCT装置を集約して、X-Earthセンターという組織を作っており、我々も参加して医工連携研究を進めています。これまでに、マイクロX線CT装置を使って下肢血管の構造を明らかにするなど、生体組織の特徴に応じた撮影法を確立していて、これらの技術を顕微鏡撮影技術などと並行して検討することで、微細構造の新たな定量解析法の開発を目指します。


X-Earth center:

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