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社会的ジェットラグは循環するプロラクチンリズムの乱れを介した肝脂質代謝の概日リモデリングにより脂肪肝を誘発する

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

Peng-Zi Zhang12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    National Key Laboratory for Novel Software Technology and the National Institute of Healthcare Data Science, Nanjing University, Nanjing 210008, China

Ying-Huan Shi3,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

Yu-Xin Guo12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    National Key Laboratory for Novel Software Technology and the National Institute of Healthcare Data Science, Nanjing University, Nanjing 210008, China

Ya-Yuan Li3,  
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

Hong-Li Yin12,  
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

Tian-Yu Wu12,  
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

Ye Zhu12,  
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

Jia-Xuan Jiang12,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China

    Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing 210008, China

  • Email：biyan@nju.edu.cn
  • Introduction：* Yan Bi biyan@nju.edu.cn
Yan Bi12*

サマリー

背景 日周リズムのずれ、特に社会的ジェットラグ（SJL）の普及は、代謝障害の流行に大きく寄与しています。しかし、SJLが肝臓に及ぼす正確な影響は十分に解明されていません。方法 SJLの被験者およびSJL状態のマウスにおける循環プロラクチン（PRL）のリズミシティを評価しました。野生型およびPrl−/−マウスのジェットラグモデルを用いて、SJLが脂肪肝に与える因果メカニズムを検討しました。ルシフェラーゼレポーターアッセイ、電気泳動移動度シフトアッセイ、クロマチン免疫沈降解析を用いて、レチノイン酸受容体関連オーファン受容体αによるPRLの転写機構を研究しました。ヒトおよびマウス肝臓のRNA-seqおよび概日リズム解析を用いて、SJLに関連する非同期PRLが肝脂質代謝に与えるメカニズムを調査しました。異なる時間点におけるSJL誘導マウスへのPRL介入の治療効果を比較しました。結果 SJLは血清PRLリズムの破綻を介して、代謝機能障害関連脂肪性肝疾患（MASLD）のリスクを増加させます。特に、SJLは下垂体におけるPRLのリズミックな転写を抑制し、循環におけるPRLレベルの非同期を引き起こします。ジェットラグ条件下では、肝臓のPRLシグナル経路のリズミシティが著しく減弱し、肝臓のミトジェン活性化プロテインキナーゼ/サイクリンD1の発現抑制による脂質合成の増加をもたらしました。特に、PRLの最低値時におけるPRL投与は、ジェットラグ状態のマウスの肝脂質含量および肝障害マーカーを従来のPRL投与よりも大幅に減少させました。結論 SJL下における肝PRLシグナル経路の再プログラムと脂質代謝恒常性の乱れが脂肪肝の原因メカニズムであり、これは血清PRLリズムの破綻を介して媒介されます。PRLリズムの回復は、SJL誘発脂肪肝を効果的に軽減し、MASLD治療に新たな知見を提供します。

キーワード

社会的ジェットラグ;プロラクチン;概日リズム;代謝機能障害関連脂肪性肝疾患（MASLD）

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