The Regulation Mechanism of Glycine-N-methyltransferase on Liver Metabolism and Related Diseases
DU Xue-Er1, WANG Jian-Guo2, YAO Jun-Hu1, CAO Yang-Chun1,*
1 College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China;
2 College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China
Abstract：The liver, a vital functional organ of the human body, can metabolize various substances and transport them to other parts of the body for utilization and excretion. It also has a plenty of physiological functions such as detoxification and the synthesis, metabolism, digestion and storage of various substances. Among them, fat and energy metabolism are particularly important. If this process becomes abnormal, including excessive fat synthesis, reduced metabolism, and decreased transport capacity, will cause the risk of a variety of diseases such as non-alcoholic fatty liver disease, liver fibrosis and cirrhosis, cholestasis, and even liver cell carcinoma rising rapidly. Liver is also closely related to the induction of other metabolic diseases. Recent studies have declared that glycine-N-methyltransferase (GNMT) in the liver acts as a key enzyme that regulates the conversion of S-adenosylmethionine (SAM) to S-adenosyl homocysteine (SAH), which can change the in-body level of SAM and then regulates the body's methylation status. GNMT can also alter the expression of fat metabolism and transport related genes, as well as the activity of oxidative respiratory complexⅡ to regulate fat content and reduce the occurrence and further development of diseases. This review describes the regulatory effects of GNMT on lipid metabolism, glucose metabolism, and oxidative stress in the liver. The therapeutic effects of GNMT in a variety of liver diseases are also discussed. This article can lay a solid theoretical foundation for future treatment methods and targets aim to GNMT.
杜雪儿, 王建国, 姚军虎, 曹阳春. 甘氨酸-N-甲基转移酶对肝脏代谢及相关疾病的调控机制[J]. 农业生物技术学报, 2022, 30(11): 2224-2235.
DU Xue-Er, WANG Jian-Guo, YAO Jun-Hu, CAO Yang-Chun. The Regulation Mechanism of Glycine-N-methyltransferase on Liver Metabolism and Related Diseases. 农业生物技术学报, 2022, 30(11): 2224-2235.
[1] Augoustides-Savvopoulou P, Luka Z, Karyda S, et al.2003. Glycine N -methyltransferase deficiency: A new patient with a novel mutation[J]. Journal of Inherited Metabolic Disease, 26(8): 745-59.
[2] Avila M A, Berasain C, Torres L, et al.2000. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma[J]. Journal of Hepatology, 33(6): 907-14.
[3] Barbier-Torres L, Fortner K A, Iruzubieta P, et al.2020. Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation[J]. Nature Communications, 11(1): 3360.
[4] Bekdash R A.2019. Neuroprotective effects of choline and other methyl donors[J]. Nutrients, 11(12): 2995.
[5] Bertuccio P, Turati F, Carioli G, et al.2017. Global trends and predictions in hepatocellular carcinoma mortality[J]. Journal of Hepatology, 67(2): 302-309.
[6] Blumenstein J, Williams G R.1960. The enzymic N-methylation of glycine[J]. Biochemical and Biophysical Research Communications, 3: 259-263.
[7] Borowa-Mazgaj B, de Conti A, Tryndyak V, et al.2019. Gene expression and DNA methylation alterations in the glycine N-methyltransferase gene in diet-induced nonalcoholic fatty liver disease-associated carcinogenesis[J]. Toxicological Sciences, 170(2): 273-282.
[8] Cano A, Buqué X, Martínez-Uña M, et al.2011. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice[J]. Hepatology, 54(6): 1975-86.
[9] Cappel D A, Deja S, Duarte J A G, et al.2019. Pyruvate-carboxylase-mediated anaplerosis promotes antioxidant capacity by sustaining TCA cycle and redox metabolism in liver[J]. Cell Metabolism, 29(6): 1291-1305.
[10] Chen C Y, Ching L C, Liao Y J, et al.2012. Deficiency of glycine N-methyltransferase aggravates atherosclerosis in apolipoprotein E-null mice[J]. Molecular Medicine(Cambridge, Mass.), 18(1): 744-52.
[11] Chen S Y, Lin J R, Darbha R, et al.2004. Glycine N-methyltransferase tumor susceptibility gene in the benzo(a)pyrene-detoxification pathway[J]. Cancer Research, 64(10): 3617-3623.
[12] Chen Y M, Shiu J Y, Tzeng S J, et al.1998. Characterization of glycine-N-methyltransferase-gene expression in human hepatocellular carcinoma[J]. International Journal of Cancer, 75(5): 787-793.
[13] Chou W Y, Zhao J F, Chen Y M, et al.2014. Role of glycine N-methyltransferase in experimental ulcerative colitis[J]. Journal Gastroenterology Hepatology, 29(3): 494-501.
[14] Chu P Y, Wu H J, Wang S M, et al.2021. MAT2A localization and its independently prognostic relevance in breast cancer patients[J]. International Journal of Molecular Sciences, 22(10): 5382.
[15] Cook R J, Wagner C.1984. Glycine N-methyltransferase is a folate binding protein of rat liver cytosol[J]. Proceedings of the National Academy of Sciences of the USA, 81(12): 3631-3634.
[16] Cotton C A, Bernhardsgrütter I, He H, et al.2020. Underground isoleucine biosynthesis pathways in E. coli[J]. Elife, 9: e54207.
[17] Ducker G S, Rabinowitz J D.2017. One-carbon metabolism in health and disease[J]. Cell Metabolism, 25(1): 27-42.
[18] Duszka K, Gregor A, Guillou H, et al.2020. Peroxisome proliferator-activated receptors and caloric restriction-common pathways affecting metabolism, health, and longevity[J]. Cells, 9(7): 1708.
[19] Eudy B J, McDermott C E, Liu X, et al.2020. Targeted and untargeted metabolomics provide insight into the consequences of glycine-N-methyltransferase deficiency including the novel finding of defective immune function[J]. Physiological Reports, 8(18): e14576.
[20] Fang C C, Wu C F, Liao Y J, et al.2018. AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage[J]. Scientific Reports, 8(1): 13802.
[21] Fernández-Ramos D, Fernández-Tussy P, Lopitz-Otsoa F, et al.2018. MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis[J]. Cell Death and Differentiation, 9(10): 958.
[22] Fernández-Tussy P, Fernández-Ramos D, Lopitz-Otsoa F, et al.2019. MiR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease[J]. Molecular Metabolism, 29: 40-54.
[23] Filomeni G, De Zio D, Cecconi F.2015. Oxidative stress and autophagy: the clash between damage and metabolic needs[J]. Cell Death and Differentiation, 22(3): 377-388.
[24] Fling R R, Doskey C M, Fader K A, et al.2020. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice[J]. Scientific Reports, 10(1): 14831.
[25] Francque S M, Marchesini G, Kautz A, et al.2021. Non-alcoholic fatty liver disease: A patient guideline[J]. JHEP Reports, 3(5): 100322.
[26] Ganz A B, Shields K, Fomin V G, et al.2016. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis[J]. FASEB Journal, 30(10): 3321-3333.
[27] Gijbels E, Pieters A, De Muynck K, et al.2021. Rodent models of cholestatic liver disease: A practical guide for translational research[J]. Liver International, 41(4): 656-682.
[28] Gomez-Santos L, Luka Z, Wagner C, et al.2012. Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase[J]. Hepatology, 56(2): 747-759.
[29] Hedtke V, Bakovic M.2019. Choline transport for phospholipid synthesis: An emerging role of choline transporter-like protein 1[J]. Experimental Biology and Medicine (Maywood, N.J.), 244(8): 655-662.
[30] Hatle K M, Gummadidala P, Navasa N, et al.2013. MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations[J]. Molecular and Cellular Biology, 33(11): 2302-14.
[31] Held J M.2020. Redox systems biology: harnessing the sentinels of the cysteine redoxome[J]. Antioxidants & Redox Signaling, 32(10): 659-676.
[32] Hu B, Lin J Z, Yang X B, et al.2020. Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review[J]. Cell Proliferation, 53(3): e12772.
[33] Hughey C C, Trefts E, Bracy D P, et al.2018. Glycine N-methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates[J]. The Journal of Biological Chemistry, 293(30): 11944-11954.
[34] Hung J H, Li C H, Yeh C H, et al.2018. MicroRNA-224 down-regulates glycine N-methyltransferase gene expression in hepatocellular carcinoma[J]. Scientific Reports, 8(1): 12284.
[35] Hwang I, Uchida H, Dai Z, et al.2021. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification[J]. Nature Communications, 12(1): 640.
[36] Jacobson S W, Carter R C, Molteno C D, et al.2018. Efficacy of maternal choline supplementation during pregnancy in mitigating adverse effects of prenatal alcohol exposure on growth and cognitive function: A randomized, double-blind, placebo-Controlled clinical trial[J]. Alcoholism Clinical and Experimental Research, 42(7): 1327-1341.
[37] Jichitu A, Bungau S, Stanescu A MA, et al.2021. Non-alcoholic fatty liver disease and cardiovascular comorbidities: Pathophysiological links, diagnosis, and therapeutic management[J]. Diagnostics (Basel), 11(4): 689.
[38] Judge A, Dodd M S.2020. Metabolism[J]. Essays in Biochemistry, 64(4): 607-647.
[39] Kattoor A J, Pothineni N V K, Palagiri D, et al.2017. Oxidative stress in atherosclerosis[J]. Current Atherosclerosis Reports, 19(11): 42.
[40] Kant R, Yen C H, Hung J H, et al.2019. Induction of GNMT by 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside through proteasome-independent MYC downregulation in hepatocellular carcinoma[J]. Scientific Reports, 9(1): 1968.
[41] Kant R, Yen C H, Lu C K, et al.2016. Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a glycine N-methyltransferase enhancer by high-throughput screening of natural products inhibits hepatocellular carcinoma[J]. International Journal of Molecular Sciences, 17(5): 669.
[42] Kerr S J.1972. Competing methyltransferase systems[J]. The Journal of Biological Chemistry, 247: 4248-4255.
[43] Kibel A, Lukinac A M, Dambic V, et al.2020. Oxidative stress in ischemic heart disease[J]. Oxidative Medicine and Cellular Longevity, 2020: 6627144.
[44] Kubes P, Jenne C.2018. Immune responses in the liver[J]. Annual Review of Immunology, 36: 247-277.
[45] Li C H, Yen C H, Chen Y F, et al.2017. Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma[J]. International Journal of Cancer, 140(10): 2284-2297.
[46] Liao Y J, Chen T L, Lee T S, et al.2012. Glycine N-methyltransferase deficiency affects Niemann-Pick type C2 protein stability and regulates hepatic cholesterol homeostasis[J]. Molecular Medicine, 18(1): 412-422.
[47] Liao Y J, Liu S P, Lee C M, et al.2009. Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility[J]. International Journal of Cancer, 124(4): 816-826.
[48] Liu S P, Li Y S, Chen Y J, et al.2007. Glycine N-methyltransferase-/- mice develop chronic hepatitis and glycogen storage disease in the liver[J]. Hepatology, 46(5): 1413-1425.
[49] Martínez-Chantar M L, Vázquez-Chantada M, Ariz U, et al.2008. Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice[J]. Hepatology, 47(4): 1191-1199.
[50] Martínez-Uña M, Varela-Rey M, Cano A, et al.2013. Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis[J]. Hepatology, 58(4): 1296-1305.
[51] Maynard C, Cummins I, Green J, et al.2018. A bacterial route for folic acid supplementation[J]. BMC Biology, 16(1): 67.
[52] Mittal M, Siddiqui M R, Tran K, et al.2014. Reactive oxygen species in inflammation and tissue injury[J]. Antioxidants & Redox Signaling, 20(7): 1126-1167.
[53] Murray B, Barbier-Torres L, Fan W, et al.2019. Methionine adenosyltransferases in liver cancer[J]. World Journal of Gastroenterology, 25(31): 4300-4319.
[54] Nieman K M, Rowling M J, Garrow T A, et al.2004. Modulation of methyl group metabolism by streptozotocin-induced diabetes and all-trans-retinoic acid[J]. The Journal of Biological Chemistry, 279(44): 45708-45712.
[55] Ogawa H, Gomi T, Takusagawa F, et al.1998. Structure, function and physiological role of glycine N-methyltransferase[J]. The International Journal of Biochemistry & Cell Biology, 30(1): 13-26.
[56] Popay T M, Wang J, Adams C M, et al.2021. MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1[J]. Elife, 10: e60191.
[57] Romero N, Van Waesberghe C, Favoreel H W.2020. Pseudorabies virus infection of epithelial cells leads to persistent but aberrant activation of the NF-κB pathway, inhibiting hallmark NF-ĸB-induced proinflammatory gene expression[J]. Journal of Virology, 94(10): e00196-20.
[58] Rives C, Fougerat A, Ellero-Simatos S, et al.2020. Oxidative stress in NAFLD: Role of nutrients and food contaminants[J]. Biomolecules, 10(12): 1702.
[59] Rowling M J, McMullen M H, Schalinske K L.2002. Vitamin A and its derivatives induce hepatic glycine N-methyltransferase and hypomethylation of DNA in rats[J]. The Journal of Nutrition, 132(3): 365-369.
[60] Rowling M J, Schalinske K L.2003. Retinoic acid and glucocorticoid treatment induce hepatic glycine N-methyltransferase and lower plasma homocysteine concentrations in rats and rat hepatoma cells[J]. The Journal of Nutrition, 133(11): 3392-3398.
[61] Simile M M, Cigliano A, Paliogiannis P, et al.2021. Nuclear localization dictates hepatocarcinogenesis suppression by glycine N-methyltransferase[J]. Translational Oncology, 15(1): 101239.
[62] Simile M M, Latte G, Feo C F, et al.2018. Alterations of methionine metabolism in hepatocarcinogenesis: The emergent role of glycine N-methyltransferase in liver injury[J]. Annals of Gastroenterology, 31(5): 552-560.
[63] Snider S A, Margison K D, Ghorbani P, et al.2018. Choline transport links macrophage phospholipid metabolism and inflammation[J]. The Journal of Biological Chemistry, 293(29): 11600-11611.
[64] Stamataki Z, Swadling L.2020. The liver as an immunological barrier redefined by single-cell analysis[J]. Immunology, 160(2): 157-170.
[65] Vancells Lujan P, Viñas Esmel E, Sacanella Meseguer E.2021. Overview of Non-alcoholic fatty liver disease (NAFLD) and the role of sugary food consumption and other dietary components in Its development[J]. Nutrients, 13(5): 1442.
[66] Villanueva A.2019. Hepatocellular carcinoma[J]. The New England Journal of Medicine, 380(15): 1450-1462.
[67] Walker A K, Jacobs R L, Watts J L, et al.2011. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans[J]. Cell, 147(4): 840-852.
[68] Wang J, Liu Q, Yuan S, et al.2017. Genetic predisposition to lung cancer: Comprehensive literature integration, meta-analysis, and multiple evidence assessment of candidate-gene association studies[J]. Scientific Reports, 7(1): 8371.
[69] Wang Y C, Wu M T, Lin Y J, et al.2015. Regulation of folate-mediated one-carbon metabolism by glycine N-Methyltransferase (GNMT) and methylenetetrahydrofolate reductase(MTHFR)[J]. Journal of Nutritional Science and Vitaminology, 61: S148-S150.
[70] Xin F Z, Zhao Z H, Zhang R N, et al.2020. Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα[J]. World Journal of Gastroenterology, 26(18): 2203-2220.
[71] Xu H, Hu L, Liu T, et al.2020. Caffeine targets G6PDH to disrupt redox homeostasis and inhibit renal cell carcinoma proliferation[J]. Frontiers in Cell and Developmental Biology, 8: 556162.
[72] Yen C H, Lu Y C, Li C H, et al.2012. Functional characterization of glycine N-methyltransferase and its interactive protein DEPDC6/DEPTOR in hepatocellular carcinoma[J]. Molecular Medicine(Cambridge, Mass.), 18(1): 286-296.
[73] Yeo E J, Wagner C.1994. Tissue distribution of glycine N-methyltransferase, a major folate binding protein of liver[J]. Proceedings of the National Academy of Sciences of the USA, 91: 210-214.
[74] Zhang Y, Hu X, Chang J, et al.2021. The liver steatosis severity and lipid characteristics in primary biliary cholangitis[J]. BMC Gastroenterology, 21(1): 395.
