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Mammalian Target of Rapamycin Complex 2 Signaling Is Required for Liver Regeneration in a Cholestatic Liver Injury Murine Model

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机构： [1]Department of Infectious Diseases,The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China [2]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, California [3]Department of General Surgery,The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China [4]Department of Pediatrics,Zhongnan Hospital of Wuhan University, Wuhan, PR China [5]Hepatic Surgery Center,Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China [6]Clinical Medical College of Yangzhou University,Yangzhou, PR China [7]Liver Transplantation Division,Department of Liver Surgery,West China Hospital, Sichuan University, Chengdu, PR China [8]Laboratory of Liver Surgery,West China Hospital, Sichuan University, Chengdu, PR China [9]Center for Drug Discovery,Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas [10]Institute of Pathology,University of Regensburg, Regensburg, Germany

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Cholestatic liver injury may lead to a series of hepatobiliary syndromes, which can progress to cirrhosis and impaired liver regeneration, eventually resulting in liver-related death. Mammalian target of rapamycin complex 2 (mTORC2) is a major regulator of liver metabolism and tumor development. However, the role of mTORC2 signaling in cholestatic liver injury has not been characterized to date. In this study, we generated liver-specific Rictor knockout mice to block the mTORC2 signaling pathway. Mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to induce cholestatic liver injury. DDC feeding induced cholestatic liver injury and ductular reaction as well as activation of the mTORC2/Akt signaling pathway in wild-type mice. Loss of mTORC2 led to significantly decreased oval cell expansion after DDC feeding. Mechanistically, this phenotype was independent of mTORC1/fatty acid synthase cascade (Fasn) or yes-associated protein (Yap) signaling. Notch pathway was instead strongly inhibited during DDC-induced cholestatic liver injury in liver-specific Rictor knockout mice. Furthermore, mTORC2 deficiency in adult hepatocytes did not inhibit ductular reaction in this cholestatic live injury mouse model. Our results indicated that mTORC2 signaling effectively regulates liver regeneration by inducing oval cell proliferation. Liver progenitor cells or bile duct cells, rather than mature hepatocytes, would be the major source of ductular reaction in DDC-induced cholestatic liver injury. © 2020 American Society for Investigative Pathology

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出版当年[2020]版：

大类 | 2 区

医学

小类 | 2 区病理学

最新[2023]版：

大类 | 2 区医学

小类 | 2 区病理学

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出版当年[2020]版：

Q2 PATHOLOGY

最新[2023]版：

Q1 PATHOLOGY

影响因子： 4.7 最新[2023版] 4.8 最新五年平均 4.307 出版当年[2020版] 5.138 出版当年五年平均 3.491 出版前一年[2019版] 5.77 出版后一年[2021版]

第一作者：

第一作者机构： [1]Department of Infectious Diseases,The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China [2]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, California

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通讯作者：

通讯机构： [1]Department of Infectious Diseases,The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China [3]Department of General Surgery,The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, PR China [*1]Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, Shaanxi, PR China, 710061 [*2]Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 513 Parnassus Ave., S-816, San Francisco, CA 94143.

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