Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulati...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/17/10072 |
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| author | Ming-Hui Yang Wei-You Li Ching-Fen Wu Yi-Ching Lee Allan Yi-Nan Chen Yu-Chang Tyan Yi-Ming Arthur Chen |
| author_facet | Ming-Hui Yang Wei-You Li Ching-Fen Wu Yi-Ching Lee Allan Yi-Nan Chen Yu-Chang Tyan Yi-Ming Arthur Chen |
| author_sort | Ming-Hui Yang |
| collection | DOAJ |
| description | Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. 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. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:42:32Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a764c6d7a37844f18762868cfb3f48be2023-11-23T13:22:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123171007210.3390/ijms231710072Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-MethyltransferaseMing-Hui Yang0Wei-You Li1Ching-Fen Wu2Yi-Ching Lee3Allan Yi-Nan Chen4Yu-Chang Tyan5Yi-Ming Arthur Chen6Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, TaiwanLaboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanDepartment of Veterinary Medicine, National Chiayi University, Chiayi City 600, TaiwanLaboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanSchool of Medicine, University of California, Davis, Sacramento, CA 95817, USADepartment of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, TaiwanLaboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanNonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. 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. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.https://www.mdpi.com/1422-0067/23/17/10072glycine N-methyltransferasemetformin1,2,3,4,6-pentagalloyl glucosenonalcoholic fatty liver diseasemitochondria |
| spellingShingle | Ming-Hui Yang Wei-You Li Ching-Fen Wu Yi-Ching Lee Allan Yi-Nan Chen Yu-Chang Tyan Yi-Ming Arthur Chen Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase International Journal of Molecular Sciences glycine N-methyltransferase metformin 1,2,3,4,6-pentagalloyl glucose nonalcoholic fatty liver disease mitochondria |
| title | Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase |
| title_full | Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase |
| title_fullStr | Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase |
| title_full_unstemmed | Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase |
| title_short | Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase |
| title_sort | reversal of high fat diet induced non alcoholic fatty liver disease by metformin combined with pgg an inducer of glycine n methyltransferase |
| topic | glycine N-methyltransferase metformin 1,2,3,4,6-pentagalloyl glucose nonalcoholic fatty liver disease mitochondria |
| url | https://www.mdpi.com/1422-0067/23/17/10072 |
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