Zhou, Yi and Xu, Meng and Liu, Pin and Liang, Binyong and Qian, Manning and Wang, Haichuan and Song, Xinhua and Nyshadham, Pranavanand and Che, Li and Calvisi, Diego F. and Li, Feng and Lin, Shumei and Chen, Xin (2020) Mammalian Target of Rapamycin Complex 2 Signaling Is Required for Liver Regeneration in a Cholestatic Liver Injury Murine Model. AMERICAN JOURNAL OF PATHOLOGY, 190 (7). pp. 1414-1426. ISSN 0002-9440, 1525-2191
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANIMAL-MODELS; MTOR; MICE; GROWTH; CELLS; AKT2; GLUCOKINASE; CHOLANGITIS; LIPOGENESIS; INHIBITION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2021 11:03 |
| Last Modified: | 19 Mar 2021 11:03 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44314 |
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