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SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway

Wang, Menghao PhD1; Yuan, Fangchao PhD1; Bai, He MD1; Zhang, Jie MD2; Wu, Hao PhD1; Zheng, Kaiwen MD1; Zhang, Wenfeng PhD1; Miao, Mingyong PhD3; Gong, Jianping PhD1

doi: 10.1097/TP.0000000000002747
Original Basic Science—Liver
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Background. The development of liver transplantation (LT) is increasingly being limited by the unavailability of liver grafts. Unique regenerative capacity of liver in response to injuries makes living-donor liver transplantation (LDLT) a feasible strategy to meet clinical demands. Serine hydroxymethyl-transferase 2 (SHMT2) serves as the key enzyme in the biosynthesis of glycine. Glycine affects the activity of mammalian target of rapamycin (mTOR), which is important for cellular growth and proliferation. In this study, the effects of SHMT2 on mouse liver regeneration were investigated using a classical partial hepatectomy (PH) model.

Methods. In vivo, PH was performed on mice with or without knockdown of SHMT2. In vitro, SHMT2 was overexpressed in primary hepatocytes, which were cultured in customized Dulbecco’s modified eagle media and LY294002 (an Akt inhibitor). Relevant indexes of liver regeneration, cell proliferation, and Akt/mTOR signal pathways were analyzed.

Results. After PH, the expression levels of SHMT2 fluctuated with time and knockdown of SHMT2 in vivo lowered the regenerative ability of liver, with reduced glycine levels compared to the scramble group. In addition, overexpression of SHMT2 in hepatocytes boosted glycine production while enhancing Akt/mTOR pathway activity. These results were validated by the application of LY294002 in vitro.

Conclusions. SHMT2 can contribute to liver regeneration after PH, and this is likely related to the activation of Akt/mTOR signaling pathway by its metabolic product, glycine, in hepatocytes. These results might have therapeutic implications for the prognosis of patients undergoing hepatic resection or transplantation.

1 Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

2 Department of Endocrinology, The Affiliated Huai’an Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China.

3 Department of Biochemistry and Molecular Biology, The Second Military Medical University, Shanghai, China.

Received 12 November 2018. Revision received 23 February 2019.

Accepted 21 March 2019.

This work was supported by grants from the National Natural Science Foundation of China (No. 81670599 and No. 81570569).

The authors declare no conflicts of interests.

J.P.G. and M.Y.M. designed the study. M.H.W. and F.C.Y. carried out the animal experiments. W.F.Z., H.B., and M.H.W. performed the cell experiments. H.B. and H.W. conducted the molecular cloning and staining experiments. K.W.Z. and J.Z. analyzed the data. F.C.Y. and M.H.W. wrote the article. All authors have read and approved the final version of this article. M.H.W. and F.C.Y. contributed equally to this article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

(a) Correspondence: Mingyong Miao, PhD, Department of Biochemistry and Molecular Biology, The Second Military Medical University, 800 Xiangyin Rd, Shanghai 200433, China. (miaomy@163.com).

(b) Correspondence: Jianping Gong, PhD, Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Rd, Chongqing 400010, China. (gongjianping11@126.com).

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