mTORC2 Signaling Is Necessary for Timely Liver Regeneration after Partial Hepatectomy

Meng Xu; Haichuan Wang; Jingxiao Wang; Deviana Burhan; Runze Shang; Pan Wang; Yi Zhou; Rong Li; Bingyong Liang; Katja Evert; Kirsten Utpatel; Zhong Xu; Xinhua Song; Li Che; Diego F Calvisi; Bruce Wang; Xi Chen; Yong Zeng; Xin Chen

doi:10.1016/j.ajpath.2019.12.010

mTORC2 Signaling Is Necessary for Timely Liver Regeneration after Partial Hepatectomy

Am J Pathol. 2020 Apr;190(4):817-829. doi: 10.1016/j.ajpath.2019.12.010. Epub 2020 Feb 5.

Authors

Meng Xu¹, Haichuan Wang², Jingxiao Wang³, Deviana Burhan⁴, Runze Shang⁵, Pan Wang⁶, Yi Zhou⁷, Rong Li⁸, Bingyong Liang⁹, Katja Evert¹⁰, Kirsten Utpatel¹⁰, Zhong Xu¹¹, Xinhua Song¹², Li Che¹², Diego F Calvisi¹⁰, Bruce Wang⁴, Xi Chen¹³, Yong Zeng¹⁴, Xin Chen¹⁵

Affiliations

¹ Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China; Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California.
² Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, PR China; Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, PR China; Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
³ Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, PR China.
⁴ Department of Medicine, Liver Center, University of California, San Francisco, California.
⁵ Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, PR China.
⁶ Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, Beijing, PR China.
⁷ Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
⁸ Department of Anesthesiology, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
⁹ Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California; Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
¹⁰ Institute of Pathology, University of Regensburg, Regensburg, Germany.
¹¹ Department of Gastroenterology, Guizhou Provincial People's Hospital, Medical College of Guizhou University, Guiyang, PR China.
¹² Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California.
¹³ Department of General Surgery, The Second Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China.
¹⁴ Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, PR China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, PR China. Electronic address: [email protected].
¹⁵ Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California. Electronic address: [email protected].

Abstract

Liver regeneration is a fundamental biological process required for sustaining body homeostasis and restoring liver function after injury. Emerging evidence demonstrates that cytokines, growth factors, and multiple signaling pathways contribute to liver regeneration. Mammalian target of rapamycin complex 2 (mTORC2) regulates cell metabolism, proliferation and survival. The major substrates for mTORC2 are the AGC family members of kinases, including AKT, SGK, and PKC-α. We investigated the functional roles of mTORC2 during liver regeneration. Partial hepatectomy (PHx) was performed in liver-specific Rictor (the pivotal unit of mTORC2 complex) knockout (Rictor^LKO) and wild-type (Rictor^fl/fl) mice. Rictor-deficient mice were found to be more intolerant to PHx and displayed higher mortality after PHx. Mechanistically, loss of Rictor resulted in decreased Akt phosphorylation, leading to a delay in hepatocyte proliferation and lipid droplets formation along liver regeneration. Overall, these results indicate an essential role of the mTORC2 signaling pathway during liver regeneration.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle Checkpoints
Cell Proliferation*
Female
Hepatectomy*
Lipids / analysis
Liver / cytology*
Liver / metabolism
Liver / surgery
Liver Regeneration*
Male
Mechanistic Target of Rapamycin Complex 2 / genetics
Mechanistic Target of Rapamycin Complex 2 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Rapamycin-Insensitive Companion of mTOR Protein / physiology*
Signal Transduction

Substances

Lipids
Rapamycin-Insensitive Companion of mTOR Protein
rictor protein, mouse
Mechanistic Target of Rapamycin Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding