PMID- 35212811
OWN - NLM
STAT- MEDLINE
DCOM- 20220608
LR  - 20220621
IS  - 1438-2199 (Electronic)
IS  - 0939-4451 (Linking)
VI  - 54
IP  - 5
DP  - 2022 May
TI  - The role of SHMT2 in modulating lipid metabolism in hepatocytes via 
      glycine-mediated mTOR activation.
PG  - 823-834
LID - 10.1007/s00726-022-03141-9 [doi]
AB  - Serine hydroxymethyltransferase 2 (SHMT2) converts serine into glycine in the 
      mitochondrial matrix, transferring a methyl group to tetrahydrofolate. SHMT2 
      plays an important role in the maintenance of one-carbon metabolism. Previously, 
      we found a negative correlation between the serine concentration and the 
      progression of fatty liver disease (FLD). However, little is known about the role 
      of SHMT2 in hepatic lipid metabolism. We established SHMT2 knockdown (KD) mouse 
      primary hepatocytes using RNA interference to investigate the role of SHMT2 in 
      lipid metabolism. SHMT2 KD hepatocytes showed decreased lipid accumulation with 
      reduced glycine levels compared to the scramble cells, which was restored upon 
      reintroducing SHMT2. SHMT2 KD hepatocytes showed downregulation of the mTOR/PPARɣ 
      pathway with decreased gene expression related to lipogenesis and fatty acid 
      uptake. Pharmacological activation of mTOR or PPARɣ overexpression blocked the 
      inhibitory effect of SHMT2 KD on lipid accumulation. We also showed that glycine 
      activated mTOR/PPARɣ signaling and identified glycine as a mediator of 
      SHMT2-responsive lipid accumulation in hepatocytes. In conclusion, silencing 
      SHMT2 in hepatocytes ameliorates lipid accumulation via the glycine-mediated 
      mTOR/PPARɣ pathway. Our findings underscore the possibility of SHMT2 as a 
      therapeutic target of FLD.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, 
      part of Springer Nature.
FAU - Choi, You-Jin
AU  - Choi YJ
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Lee, Geunhye
AU  - Lee G
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Yun, Sung Ho
AU  - Yun SH
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Lee, Wonseok
AU  - Lee W
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Yu, Jieun
AU  - Yu J
AD  - College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
FAU - Kim, Sang Kyum
AU  - Kim SK
AD  - College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
FAU - Lee, Byung-Hoon
AU  - Lee BH
AUID- ORCID: 0000-0002-0348-4675
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea. lee@snu.ac.kr.
LA  - eng
GR  - 2020R1A2B5B01001920/National Research Foundation of Korea/
GR  - 2021R1C1C2004529/National Research Foundation of Korea/
PT  - Journal Article
DEP - 20220225
PL  - Austria
TA  - Amino Acids
JT  - Amino acids
JID - 9200312
RN  - 0 (Lipids)
RN  - 0 (PPAR gamma)
RN  - 452VLY9402 (Serine)
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.- (Shmt2 protein, mouse)
RN  - EC 2.1.2.1 (Glycine Hydroxymethyltransferase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Animals
MH  - *Glycine/metabolism
MH  - *Glycine Hydroxymethyltransferase/genetics/metabolism
MH  - Hepatocytes/metabolism
MH  - Hydroxymethyl and Formyl Transferases
MH  - Lipid Metabolism
MH  - Lipids
MH  - Mice
MH  - PPAR gamma/metabolism
MH  - Serine/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
OTO - NOTNLM
OT  - Glycine
OT  - Lipid metabolism
OT  - PPARɣ
OT  - SHMT2
OT  - mTOR
EDAT- 2022/02/26 06:00
MHDA- 2022/06/09 06:00
CRDT- 2022/02/25 12:23
PHST- 2021/10/22 00:00 [received]
PHST- 2022/02/09 00:00 [accepted]
PHST- 2022/02/26 06:00 [pubmed]
PHST- 2022/06/09 06:00 [medline]
PHST- 2022/02/25 12:23 [entrez]
AID - 10.1007/s00726-022-03141-9 [pii]
AID - 10.1007/s00726-022-03141-9 [doi]
PST - ppublish
SO  - Amino Acids. 2022 May;54(5):823-834. doi: 10.1007/s00726-022-03141-9. Epub 2022 
      Feb 25.