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Controlled lipid β-oxidation and carnitine biosynthesis by a vitamin D metabolite

MENDOZA, AILEEN DE LEON 京都大学 DOI:10.14989/doctor.k24287

2022.11.24

概要

(目的)ビタミンDは、日光を浴びることで体内で合成され、骨代謝調節、筋肉、免疫調節等で重要な働きをする。ビタミンDラクトンは、ビタミンDの主要な最終代謝産物として約40年前に発見されたが、その生物学的役割はほとんどわかっていなかった。そこで、本研究では、ビタミンDラクトンの生体内での役割を明らかにすることを目的とした。

(方法と結果)まずビタミンDラクトンの標的タンパク質を、その光親和性標識プローブを用いて探索した。その結果、ヒドロキシアシル-CoAデヒドロゲナーゼサブユニット(HADHA)を結合タンパク質として同定した。HADHAは、ミトコンドリア内で長鎖脂肪酸のβ酸化を触媒する酵素である。ところが、興味深いことに、ビタミンDラクトンはHADHAと相互作用するにも関わらず、HADHAの酵素活性に影響しなかった。そこで、ビタミンDラクトンの役割を詳細に解析したところ、ビタミンDラクトンはHADHAに結合することで、HADHAとカルニチン生合成酵素トリメチルリジンジオキシゲナーゼ(TMLD)との相互作用を阻害し、カルニチン生合成を抑制することを見出した。カルニチンは、β酸化のために脂肪酸をミトコンドリアへ輸送するのに必要な内因性代謝物である。以上の結果より、ビタミンDラクトンは、HADHAと結合することでカルニチンの生合成を抑制し、脂肪酸のβ酸化を抑制することが明らかとなった。

(考察)本研究により、ビタミンDラクトンが脂肪酸のβ酸化を抑制する、すなわち脂肪酸を体内に貯めこむ働きがあることが示唆された。生合成されるビタミンDの量は日光の暴露量が多い夏季に最大となることが知られており、その代謝物であるビタミンDラクトンの量も季節変動すると考えられる。ビタミンDからビタミンDラクトンへの代謝量は生物種にも依存するが、季節で日照時間が大きく変わる高緯度地域に生息する動物では、ビタミンDラクトンが脂肪酸代謝を変化させる季節変動因子の一つであると推測される。

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