Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH

Persistent ID (NDL): info:ndljp/pid/12263754

Material type: 博士論文

Author: Yoshida, Tomoaki

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Publication date: 2021-03-23

Material Format: Digital

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Name of awarding university/degree: 新潟大学,博士（医学）

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Note (General)：: The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aim...

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Material Type: 博士論文
Title: Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH
Author/Editor: Yoshida, Tomoaki
Author Heading: Yoshida, Tomoaki
Publication Date: 2021-03-23
Publication Date (W3CDTF): 2021-03-23
Alternative Title: NASHモデルマウスにおいて、スフィンゴシン1リン酸受容体2の阻害は肝細胞がんの進を促す
Degree grantor/type: 新潟大学
Date Granted: 2021-03-23
Date Granted (W3CDTF): 2021-03-23
Dissertation Number: 甲第4823号
Degree Type: 博士（医学）
Conferring No. (Dissertation): 甲第4823号
Text Language Code: eng
Alias of Author: 吉田, 智彰
Subject Heading: JTE-013
S-adenosyl-L-methionine
Melanocortin-4 receptor
S1P-Specific G protein-coupled receptor 2
Glycine N-Methyltransferase
Target Audience: 一般
Note (General): The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aimed to analyze the role of S1P/S1PRs in a Melanocortin-4 receptor (Mc4r)-deficient NASH murine model using FTY720, the functional antagonist of S1PR1, S1PR3, S1PR4, and S1PR5, and JTE-013, the antagonist of S1PR2. We observed that, compared to that in the control, the mRNA of S1pr1 tended to decrease, whereas those of S1pr2 and S1pr3 significantly increased in Mc4r-knockout (KO) mice subjected to a Western diet (WD). While the fat area did not differ, fibrosis progression differed significantly between control mice and mice in which liver S1PRs were blocked. Lipidomic and metabolomic analysis of liver tissues showed that JTE-013-administered mice showed elevation of S-adenosyl-L-methionine level, which can induce aberrant methylation due to reduction in glycine N-methyltransferase (GNMT) and elevation in diacylglycerol (DG) and triacylglycerol (TG) levels, leading to increased susceptibility to hepatocellular carcinoma (HCC). These phenotypes are similar to those of Gnmt-KO mice, suggesting that blocking the S1P/S1PR2 axis triggers aberrant methylation, which may increase DG and TG, and hepatocarcinogenesis. Our observations that the S1P/S1PR2 axis averts HCC occurrence may assist in HCC prevention in NASH.
Biochemical and Biophysical Research Communications. 2020, 530(4), 665-672.
新大院博(医)第977号
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https://dl.ndl.go.jp/collections/A00014
Acquisition Basis: 博士論文（自動収集）
Date Accepted (W3CDTF): 2022-05-09T11:57:37+09:00
Format (IMT): application/pdf
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Periodical Title (URI): http://hdl.handle.net/10191/0002000282
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