國家衛生研究院 NHRI:Item 3990099045/15516
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    题名: Therapeutic effects of gnmt inducers for non-alcoholic fatty liver disease and hepatocellular carcinoma
    作者: Chen, Y
    贡献者: National Institute of Infectious Diseases and Vaccinology
    摘要: Background: Glycine-N-methyl transferase (GNMT) downregulation results in nonalcoholic fatty liver disease (NAFLD) and spontaneous hepatocellular carcinoma (HCC) both. Overexpression of GNMT inhibits the accumulation of lipid in hepatocytes, the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is potential approaches for anti-NAFLD and anti-HCC therapy. Methods: Herein, we used Huh7 GNMT promoter-driven screening to identify two GNMT inducers from natural plant extracts library and small molecule library. First, 1,2,3,4,6-pentagalloyl glucose (PGG) was identified from the extract of Paeonia lactiflora Pall (PL). Second, compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure−activity relationship analysis and found a potent GNMT inducer, K117. The GNMT expression was further confirmed by reverse transcription-quantitative PCR (RT-qPCR) and Western blotting (WB) analysis using both in vitro and in vivo systems. Results: PGG and metformin were shown to upregulate liver mitochondrial GNMT protein expression. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. The combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. On the other hand, K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib. A mechanistic study revealed that both PGG and K117 are MYC inhibitors. Ectopic expression of MYC using CMV promoter blocked PGG- and K117-mediated MYC inhibition and GNMT induction. Conclusion: Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD and HCC, PGG and K117 are potential compounds for NAFLD-, HCC- and MYC-dependent cancers.
    日期: 2023-10
    關聯: Hepatology. 2023 Oct;78(Suppl. 1):S1903.
    Link to: http://dx.doi.org/10.1097/HEP.0000000000000580
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0270-9139&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001094865404407
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