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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.<\/jats:p>","DOI":"10.3390\/ijms231710072","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10072","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-0498","authenticated-orcid":false,"given":"Ming-Hui","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"},{"name":"Center of General Education, Shu-Zen Junior College of Medicine and Management, Kaohsiung 821, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-You","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Fen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, National Chiayi University, Chiayi City 600, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ching","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan Yi-Nan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, University of California, Davis, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-5893","authenticated-orcid":false,"given":"Yu-Chang","family":"Tyan","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan"},{"name":"School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ming Arthur","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"},{"name":"National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8263","DOI":"10.3748\/wjg.v23.i47.8263","article-title":"Clinical epidemiology and disease burden of nonalcoholic fatty liver disease","volume":"23","author":"Perumpail","year":"2017","journal-title":"World J. 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