グルカゴンはINSP3R1媒介による肝臓脂解によってグルコネオゲネシスを刺激する
Rachel J Perry1,2, Dongyan Zhang1, Mateus T Guerra1
1Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Nature
|March 6, 2020
まとめ
グルカゴンはINSP3R1を通じて肝臓の脂肪燃焼とグルコース生成を刺激する. この受容体をターゲットにすることで 脂肪肝と2型糖尿病を逆転させることができます
科学分野:
- 代謝 疾患
- ヘパトロジー
- 内分泌学
背景:
- 低インスリン/ グルカゴン比は2型糖尿病における肝臓のグルコース代謝に影響する.
- 肝臓のグルコース生成とミトコンドリアの酸化に対するグルカゴンの作用のメカニズムは不明である.
研究 の 目的:
- グルカゴンが肝臓のグルコース生成とミトコンドリアの酸化に影響を与えるメカニズムを解明する.
- グルカゴンの肝臓効果を媒介するイノシトール三酸受容体1 (INSP3R1) の役割を調査する.
- 非アルコール性脂肪肝症と2型糖尿病におけるINSP3R1を標的とした治療の可能性を評価する.
主な方法:
- 肝臓脂肪トリグリセリドリパース活性,肝臓内リポリス,アセチル-CoA含量,およびピルバートカルボキシラーゼ流量に対するグルカゴンの効果を研究した.
- グルカゴンに対する反応としてミトコンドリア脂肪の酸化を調べた.
- INSP3R1 (Itpr1) - ノックアウトマウスを利用して,グルカゴンの効果を媒介するINSP3R1の必要性を評価した.
- ダイエットによる肥満マウスとラットに慢性的なグルカゴン投与.
主要な成果:
- グルカゴンはINSP3R1を活性化することで肝臓のグルコネオゲネシスとミトコンドリアの脂肪酸化を刺激する.
- ネズミの慢性的なグルカゴン治療は,食事による肝硬変とインスリン抵抗性を逆転させた.
- これらの有益な効果はINSP3R1ノックアウトマウスで廃止され,受容体の重要な役割が確認されました.
結論:
- INSP3R1によるグルカゴン信号は肝臓脂肪の酸化とグルコネオゲネシスを強化する.
- グルカゴンによるINSP3R1の活性化は,肝硬変を逆転させ,グルコース不耐性を改善することができます.
- INSP3R1は,非アルコール性脂肪肝症と2型糖尿病の潜在的な治療標的として浮上しています.
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