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Selective trans-omic regulation of insulin action by its doses across the multiple-omic layers

川田, 健太郎 東京大学 DOI:10.15083/0002001505

2021.09.08

概要

序論
生体内では多くのホルモンが協調的に作用することで、多くの生体機能が制御される。インスリンは血糖値低下に関与する唯一のホルモンであり、インスリン抵抗性などの代謝異常に起因する疾患の増加は、近年の大きな社会問題となっている (Zimmet et al., 2001)。インスリンによる細胞機能制御機構を理解することにより、インスリンの機能異常に起因する代謝障害の予防や治療に繋がる知見を得ることが可能となる。血中インスリン濃度は体内の栄養状態により異なる時間パターンを示す。これは摂食直後に認められる高濃度で一過的な変動を特徴とする追加分泌と、空腹時に認められる低濃度で持続的な変動を示す基礎分泌とに大別される (Polonsky et al., 1988) (Fig. 1 left)。過去に当研究室ではインスリンの制御を受ける分子が各々の感受性や時定数に応じて時間パターン選択的な応答を示すことを明らかにしている (Kubota et al., 2012; Noguchi et al., 2013; Sano et al., 2016)。しかしながら、インスリンの情報伝達ネットワークに含まれる分子がインスリンの基礎分泌と追加分泌のどちらに選択的に応答するかについて網羅的に明らかにした例はない。

結果と考察
本研究では複数のオミクスデータを用いて、インスリンの情報を伝えるネットワーク (trans-omic regulatory network) を構築し、さらに各分子のインスリン濃度に対する感受性を推定することにより、インスリン濃度に対する各分子の選択性を解明した。

初めにインスリン刺激を施したラット肝がん由来 Fao 細胞からリン酸化プロテオームデータ、トランスクリプトームデータ、メタボロームデータを時系列で取得した。初めに、リン酸化プロテオームデータを用いてリン酸化を介した細胞機能制御ネットワーク(cellular functions regulatory network) を再構築した。次に、リン酸化プロテオームおよびトランスクリプトームデータを用いて転写因子を介した遺伝子発現制御ネットワーク (transcriptional regulatory network) を再構築した。最後に、リン酸化プロテオームおよびメタボロームデータを用いてリン酸化を介した代謝制御ネットワーク (metabolism regulatory network) を再構築した。これらを統合することで、インスリンによる細胞機能制御ネットワークである trans-omic regulatory network を構築した (Fig. 2)。

Trans-omic regulatory network 内の各分子に対してインスリンへの感受性および時定数を推定し、各分子の追加分泌および基礎分泌に対する選択性を明らかにした。感受性の指標として EC50、および応答速度の指標として T1/2 を算出した。感受性の低い分子は刺激濃度に対し広いダイナミックレンジを示し、追加分泌への応答を示す。また感受性の高い分子は狭いダイナミックレンジを示し、主に基礎分泌に応答する (Fig. 1 right)。これらの指標によりシグナル伝達分子、発現変動遺伝子、変動代謝物を 4 クラスに分け、インスリンに対する各分子の応答性を推定した (Fig. 3)。シグナル伝達分子について、インスリンシグナル伝達のハブ分子であるAkt およびErk のリン酸化は、広範囲のインスリン濃度への応答が認められ、広いインスリン濃度の情報を下流に伝達することが示唆された。遺伝子発現について、転写因子や脂質代謝酵素を含む増加性遺伝子は広いダイナミックレンジを示し、追加分泌に対する応答を示す一方で、糖代謝酵素を含む減少性遺伝子はインスリン濃度に対して狭いダイナミックレンジを示し、主に基礎分泌への応答を示した。代謝物について、解糖系に含まれる対代謝物は主に基礎分泌に応答するが、TCA 回路に含まれる dicarboxylic acids は主に追加分泌に応答した。また解糖系上流と下流ではインスリンに対する応答速度に違いが認められた。アミノ酸の多くが主に基礎分泌に応答する一方で、解糖系からの反応距離の近い Ser、Ala、Arg は主に追加分泌への応答を示した。

まとめ
本研究ではインスリン刺激に対する情報伝達ネットワークを網羅的に再構築し、さらにネットワークに含まれる分子がインスリンの追加分泌と基礎分泌のどちらに選択的に応答するかを感受性の見地から網羅的に推定した。本研究で用いた手法は細胞や刺激の種類に依存するものではなく、さまざまなホルモンやサイトカインに対して適用が可能である。生体内における細胞間伝達物質の濃度および時間的挙動と、各分子の感受性や時定数と比較することにより、特定の条件下における各経路もしくは分子の選択性を推定することが可能となる。

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