PMID- 30964837
OWN - NLM
STAT- MEDLINE
DCOM- 20200601
LR  - 20211204
IS  - 1534-6080 (Electronic)
IS  - 0041-1337 (Linking)
VI  - 103
IP  - 7
DP  - 2019 Jul
TI  - SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway.
PG  - e188-e197
LID - 10.1097/TP.0000000000002747 [doi]
AB  - 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.
FAU - Wang, Menghao
AU  - Wang M
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Yuan, Fangchao
AU  - Yuan F
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Bai, He
AU  - Bai H
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Zhang, Jie
AU  - Zhang J
AD  - Department of Endocrinology, The Affiliated Huai'an Hospital of Xuzhou Medical 
      College, Xuzhou, Jiangsu, China.
FAU - Wu, Hao
AU  - Wu H
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Zheng, Kaiwen
AU  - Zheng K
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Zhang, Wenfeng
AU  - Zhang W
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
FAU - Miao, Mingyong
AU  - Miao M
AD  - Department of Biochemistry and Molecular Biology, The Second Military Medical 
      University, Shanghai, China.
FAU - Gong, Jianping
AU  - Gong J
AD  - Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing 
      Medical University, Chongqing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.- (Shmt2 protein, mouse)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Animals
MH  - *Cell Proliferation
MH  - Cells, Cultured
MH  - Enzyme Activation
MH  - Gene Knockdown Techniques
MH  - Glycine/*metabolism
MH  - Hepatectomy
MH  - Hepatocytes/*enzymology/pathology
MH  - Hydroxymethyl and Formyl Transferases/deficiency/genetics/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Liver/*enzymology/pathology/surgery
MH  - *Liver Regeneration
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
EDAT- 2019/04/10 06:00
MHDA- 2020/06/02 06:00
CRDT- 2019/04/10 06:00
PHST- 2019/04/10 06:00 [pubmed]
PHST- 2020/06/02 06:00 [medline]
PHST- 2019/04/10 06:00 [entrez]
AID - 10.1097/TP.0000000000002747 [doi]
PST - ppublish
SO  - Transplantation. 2019 Jul;103(7):e188-e197. doi: 10.1097/TP.0000000000002747.