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研究分野生物医学と臨床科学腫瘍学とがん発生分子標的
マウスにおける非アルコール性脂肪肝の抑制 mTORC1の選択的抑制

マウスにおける非アルコール性脂肪肝の抑制 mTORC1の選択的抑制

Bridget S Gosis ¹, Shogo Wada ¹, Chelsea Thorsheim ¹, Kristina Li ¹, Sunhee Jung ², Joshua H Rhoades ^1,3,4, Yifan Yang ¹, Jeffrey Brandimarto ¹, Li Li ¹, Kahealani Uehara ^5,6, Cholsoon Jang ², Matthew Lanza ⁷, Nathan B Sanford ¹, Marc R Bornstein ¹, Sunhye Jeong ¹, Paul M Titchenell ^5,6, Sudha B Biddinger ⁸, Zoltan Arany ¹

Bridget S Gosis ¹, Shogo Wada ¹, Chelsea Thorsheim ¹

¹Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²Department of Biological Chemistry, University of California, Irvine, CA, USA.
³Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

⁰Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Science (New York, N.Y.) +

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2022年4月14日

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PubMedで要約を見る

まとめ

この要約は機械生成です。

mTORC1経路の選択的阻害は,転写因子E3 (TFE3) を活性化することによって,非アルコール性脂肪肝 (NAFLD) と非アルコール性脂肪肝炎 (NASH) に対して保護し,潜在的な新しい治療法を提供します.

科学分野

ヘパトロジー
分子生物学
代謝疾患

背景

非アルコール性脂肪肝症 (NAFLD) と非アルコール性脂肪肝炎 (NASH) には効果的な治療法がない.
ラパミシン複合体1 (mTORC1) 経路の脂質恒常性におけるメカニズム的ターゲットは議論されており,治療ターゲティングに挑戦しています.

研究の目的

NAFLDとNASHにおける選択的なmTORC1阻害の役割を調査する.
mTORC1のシグナリングが肝臓の脂質代謝と疾患進行に影響を与えるメカニズムを解明する.

主な方法

RagC/ D GTPase活性化タンパク質であるフォリキュリン (FLCN) を選択的に消去したマウスモデルを使用して,肝臓のmTORC1シグナル伝達を阻害しました.
転写因子E3 (TFE3) の活性化および脂質代謝および肝臓病理に対するその下流効果に対するFLCN消去の影響を評価した.
TFE3とステロール調節要素結合タンパク質-1c (SREBP-1c) の相互作用を研究した.

主要な成果

選択的肝臓mTORC1阻害は,他のmTORC1標的に影響を与えることなく,FLCNの消去によってTFE3の活性化をもたらした.
この選択的抑制は,マウスのNAFLDとNASHに対する保護を与えました.
TFE3は,SREBP- 1cの処理とクロマチンの相互作用を抑制することによって,脂質の消費を増加させ,脂質生成を抑制することによって,保護を媒介した.

結論

肝臓のmTORC1シグナリングの選択的抑制はNAFLDとNASHの有効な治療戦略です.
選択的mTORC1阻害の下流のTFE3活性化は肝臓保護の重要な媒介である.
この研究は,mTORC1の脂質恒常性における役割に関する矛盾した発見を調和させ,新しい治療標的を特定した.

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Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes

Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes

Published on: September 9, 2021

Optimized Analysis of <em>In Vivo</em> and <em>In Vitro</em> Hepatic Steatosis

Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis

Published on: March 11, 2017

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関連する概念動画

mTOR Signaling and Cancer Progression

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...

PI3K/mTOR/AKT Signaling Pathway

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...

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