
The relationship between folic acid and nonalcoholic fatty liver disease
Bing'er Xu, Xinyu Yang, Xiaopeng Zhu, Qiling Liu, Yuying Zhang, Miao Zhang, Chenmin Fan, Xilei Ban, Guligeina Aikebaier, Hua bian
Clinical and Translational Discovery ›› 2024, Vol. 4 ›› Issue (1) : e274.
The relationship between folic acid and nonalcoholic fatty liver disease
In recent years, the incidence of non-alcoholic fatty liver disease (NAFLD) has been increasing, which has become an explosive interest because of the growing impact on world health. NAFLD is the hepatic manifestation of systemic metabolic syndrome (MS), and the umbrella term that comprises a continuum of liver conditions, from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and hepatocellular carcinoma (HCC). currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folic acid (FA) was one of a water-soluble B vitamins, entirely absorbed from the diet. Numbers of clinical studies have confirmed that patients with NAFLD and insulin resistance are often accompanied by abnormal FA. We investigated the potential effects of FA on NAFLD through the metabolic pathways, DNA synthesis and methylation, oxidative stress in liver and intestinal flora. In addition, FA has an effect on HCC or other cancer. Therefore, FA might be a safe and economical potential treatment method for NAFLD.
[1] |
FriedmanSL, Neuschwander-Tetri BA, RinellaM, SanyalAJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-922.
|
[2] |
WangXJ, MalhiH. Nonalcoholic fatty liver disease. Ann Intern Med. 2018;169(9):ITC65-ITC80.
|
[3] |
NegiCK, BabicaP, BajardL, Bienertova-Vasku J, TarantinoG. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism. 2022;126:154925.
|
[4] |
TarantinoG, Balsano C, SantiniSJ, et al. It is high time physicians thought of natural products for alleviating NAFLD. Is there sufficient evidence to use them. Int J Mol Sci. 2021;22(24):13424.
|
[5] |
NilssonE, MatteA, PerfilyevA, et al. Epigenetic alterations in human liver from subjects with type 2 diabetes in parallel with reduced folate levels. J Clin Endocrinol Metab. 2015;100(11):E1491-E1501.
|
[6] |
MbaCM, Koulman A, ForouhiNG, et al. Associations of serum folate and holotranscobalamin with cardiometabolic risk factors in rural and urban cameroon. Nutrients. 2021;14(1):178.
|
[7] |
AkbariM, Tabrizi R, LankaraniKB, et al. The effects of folate supplementation on diabetes biomarkers among patients with metabolic diseases: a systematic review and meta-analysis of randomized controlled trials. Horm Metab Res. 2018;50(2):93-105.
|
[8] |
Ramos-LopezO, Samblas M, MilagroFI, et al. Association of low dietary folate intake with lower CAMKK2 gene methylation, adiposity, and insulin resistance in obese subjects. Nutr Res. 2018;50:53-62.
|
[9] |
ChenX, LuJ, XuQ, ChenB, ShenL. The association between serum folate and ultrasound—defined hepatic steatosis. Ann Med. 2023;55(1):456-462.
|
[10] |
YuanS, ChenJ, DanL, et al. Homocysteine, folate, and nonalcoholic fatty liver disease: a systematic review with meta-analysis and Mendelian randomization investigation. Am J Clin Nutr. 2022;116(6):1595-1609.
|
[11] |
MahamidM, Mahroum N, BragazziNL, et al. Folate and B12 levels correlate with histological severity in NASH patients. Nutrients. 2018;10(4):440.
|
[12] |
SetolaE, MontiLD, GalluccioE, et al. Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia. Eur J Endocrinol. 2004;151(4):483-489.
|
[13] |
ZhuJ, ChenC, LuL, Shikany JM, D'AltonME, FolateKaheK. Vitamin B6, and vitamin B12 status in association with metabolic syndrome incidence. JAMA Netw Open. 2023;6(1):e2250621.
|
[14] |
SidV, SiowYL, KarminO. Role of folate in nonalcoholic fatty liver disease. Can J Physiol Pharmacol. 2017;95(10):1141-1148.
|
[15] |
SelhubJ, PaulL. Folic acid fortification: why not vitamin B12 also. Biofactors. 2011;37(4):269-271.
|
[16] |
MorrowGP, MacMillan L, LamarreSG, et al. In vivo kinetics of formate metabolism in folate-deficient and folate-replete rats. J Biol Chem. 2015;290(4):2244-2250.
|
[17] |
MacMillanL, Tingley G, YoungSK, et al. Cobalamin deficiency results in increased production of formate secondary to decreased mitochondrial oxidation of one-carbon units in rats. J Nutr. 2018;148(3):358-363.
|
[18] |
KoplayM, GulcanE, OzkanF. Association between serum vitamin B12 levels and the degree of steatosis in patients with nonalcoholic fatty liver disease. J Investig Med. 2011;59(7):1137-1140.
|
[19] |
LiL, HuangQ, YangL, et al. The Association between non-alcoholic fatty liver disease (NAFLD) and advanced fibrosis with serological vitamin B12 markers: results from the NHANES 1999–2004. Nutrients. 2022;14(6):1224.
|
[20] |
AleliunasRE, Aljaadi AM, LaherI, et al. Folic acid supplementation of female mice, with or without vitamin B-12, before and during pregnancy and lactation programs adiposity and vascular health in adult male offspring. J Nutr. 2015;146(4):688-696.
|
[21] |
LiuY, ShenJ, YangX, Sun Q, YangX. Folic acid reduced triglycerides deposition in primary chicken hepatocytes. J Agric Food Chem. 2018;66(50):13162-13172.
|
[22] |
IllingworthRS, BirdAP. CpG islands–a rough guide. FEBS Lett. 2009;583(11):1713-1720.
|
[23] |
VachherM, BansalS, KumarB, Yadav S, BurmanA. Deciphering the role of aberrant DNA methylation in NAFLD and NASH. Heliyon. 2022;8(10):e11119.
|
[24] |
SkvortsovaK, IovinoN, BogdanovićO. Functions and mechanisms of epigenetic inheritance in animals. Nat Rev Mol Cell Biol. 2018;19(12):774-790.
|
[25] |
KloseRJ, BirdAP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31(2):89-97.
|
[26] |
FinerS, Saravanan P, HitmanG, YajnikC. The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. Diab Med. 2014;31(3):263-272.
|
[27] |
HyunJ, JungY. DNA methylation in nonalcoholic fatty liver disease. Int J Mol Sci. 2020;21(21):8138.
|
[28] |
LiangG, ChanMF, TomigaharaY, et al. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol. 2002;22(2):480-491.
|
[29] |
PogribnyIP, Tryndyak VP, BagnyukovaTV, et al. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J Hepatol. 2009;51(1):176-186.
|
[30] |
LaiZ, ChenJ, DingC, et al. Association of hepatic global DNA methylation and serum one-carbon metabolites with histological severity in patients with NAFLD. Obesity. 2020;28(1):197-205.
|
[31] |
de OliveiraDT, de Paiva N, CarneiroCM, Guerra-SáR. Dynamic changes in hepatic DNA methylation during the development of nonalcoholic fatty liver disease induced by a high-sugar diet. J Physiol Biochem. 2022;78(4):763-775.
|
[32] |
TryndyakVP, Willett RA, AviganMI, et al. Non-alcoholic fatty liver disease-associated DNA methylation and gene expression alterations in the livers of collaborative cross mice fed an obesogenic high-fat and high-sucrose diet. Epigenetics. 2022;17(11):1462-1476.
|
[33] |
OuniM, Schürmann A. Epigenetic contribution to obesity. Mamm Genome. 2020;31(5-6):134-145.
|
[34] |
Borowa-MazgajB, de Conti A, TryndyakV, et al. Gene expression and DNA methylation alterations in the glycine N-methyltransferase gene in diet-induced nonalcoholic fatty liver disease-associated carcinogenesis. Toxicol Sci. 2019;170(2):273-282.
|
[35] |
AlshawshMA, Alsalahi A, AlshehadeSA, et al. A comparison of the gene expression profiles of non-alcoholic fatty liver disease between animal models of a high-fat diet and methionine-choline-deficient diet. Molecules. 2022;27(3):858.
|
[36] |
BuettnerR, Bettermann I, HechtlC, et al. Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome. Horm Metab Res. 2010;42(11):769-774.
|
[37] |
CorderoP, Campion J, MilagroFI, MartinezJA. Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: effect of dietary methyl donor supplementation. Mol Genet Metab. 2013;110(3):388-395.
|
[38] |
LiW, TangR, MaF, OuyangS, LiuZ, WuJ. Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice. J Nutr Biochem. 2018;59:76-83.
|
[39] |
TryndyakVP, HanT, MuskhelishviliL, et al. Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl-deficient diet. Mol Nutr Food Res. 2011;55(3):411-418.
|
[40] |
van WijkN, Watkins CJ, BöhlkeM, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 2012;107(10):1408-1412.
|
[41] |
ZhaoM, YuanMM, YuanL, et al. Chronic folate deficiency induces glucose and lipid metabolism disorders and subsequent cognitive dysfunction in mice. PLoS One. 2018;13(8):e0202910.
|
[42] |
SalmanM, KamelMA, El-NabiS, et al. The regulation of HBP1, SIRT1, and SREBP-1c genes and the related microRNAs in non-alcoholic fatty liver rats: the association with the folic acid anti-steatosis. PLoS One. 2022;17(4):e0265455.
|
[43] |
ServiddioG, Giudetti AM, BellantiF, et al. Oxidation of hepatic carnitine palmitoyl transferase-I (CPT-I) impairs fatty acid beta-oxidation in rats fed a methionine-choline deficient diet. PLoS One. 2011;6(9):e24084.
|
[44] |
PooyaS, BlaiseS, Moreno GarciaM, et al. Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α, and HNF-4α in the rat liver. J Hepatol. 2012;57(2):344-351.
|
[45] |
BaumeierC, Saussenthaler S, KammelA, et al. Hepatic DPP4 DNA methylation associates with fatty liver. Diabetes. 2017;66(1):25-35.
|
[46] |
ChangX, YanH, FeiJ, et al. Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats. J Lipid Res. 2010;51(9):2504-2515.
|
[47] |
SookoianS, Rosselli MS, GemmaC, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology. 2010;52(6):1992-2000.
|
[48] |
AhrensM, Ammerpohl O, von SchönfelsW, et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013;18(2):296-302.
|
[49] |
MurphySK, YangH, MoylanCA, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145(5):1076-1087.
|
[50] |
PirolaCJ, Gianotti TF, BurgueñoAL, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut. 2013;62(9):1356-1363.
|
[51] |
ZeybelM, HardyT, RobinsonSM, et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics. 2015;7(1):25.
|
[52] |
HottaK, Kikuchi M, KitamotoT, et al. Identification of core gene networks and hub genes associated with progression of non-alcoholic fatty liver disease by RNA sequencing. Hepatol Res. 2017;47(13):1445-1458.
|
[53] |
MwinyiJ, Boström AE, PisanuC, et al. NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862(3):314-323.
|
[54] |
WuJ, ZhangR, ShenF, et al. Altered DNA methylation sites in peripheral blood leukocytes from patients with simple steatosis and nonalcoholic steatohepatitis (NASH). Med Sci Monit. 2018;24:6946-6967.
|
[55] |
ZhangRN, PanQ, ZhengRD, et al. Genome-wide analysis of DNA methylation in human peripheral leukocytes identifies potential biomarkers of nonalcoholic fatty liver disease. Int J Mol Med. 2018;42(1):443-452.
|
[56] |
WalleP, Männistö V, de MelloVD, et al. Liver DNA methylation of FADS2 associates with FADS2 genotype. Clin Epigenetics. 2019;11(1):10.
|
[57] |
TianY, AraiE, MakiuchiS, et al. Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas. J Cancer Res Clin Oncol. 2020;146(10):2461-2477.
|
[58] |
JohnsonND, WuX, StillCD, et al. Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clin Epigenetics. 2021;13(1):152.
|
[59] |
MoylanCA, MavisAM, JimaD, et al. Alterations in DNA methylation associate with fatty liver and metabolic abnormalities in a multi-ethnic cohort of pre-teenage children. Epigenetics. 2022;17(11):1446-1461.
|
[60] |
PanX, WuY, PengH, et al. Genome-wide DNA methylation profiling in nonalcoholic fatty liver reveals predictive aberrant methylation in PRKCE and SEC14L3 promoters. Dig Liver Dis. 2022;54(4):521-528.
|
[61] |
LeeJ, SongJH, ParkJH, et al. Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis. Exp Mol Med. 2023;55(1):143-157.
|
[62] |
MeltonPE, BurtonMA, LillycropKA, et al. Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence. Hepatol Int. 2023;17:1-11.
|
[63] |
SehgalR, Perfilyev A, MännistöV, et al. Liver saturated fat content associates with hepatic DNA methylation in obese individuals. Clin Epigenetics. 2023;15(1):21.
|
[64] |
TsudaN, TianY, FujimotoM, et al. DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas. J Cancer Res Clin Oncol. 2023;149(8):5109-5125.
|
[65] |
WuYL, LinZJ, LiCC, et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study. Signal Transduct Target Ther. 2023;8(1):98.
|
[66] |
ChenHC, ChenYZ, WangCH, Lin FJ. The nonalcoholic fatty liver disease-like phenotype and lowered serum VLDL are associated with decreased expression and DNA hypermethylation of hepatic ApoB in male offspring of ApoE deficient mothers fed a with Western diet. J Nutr Biochem. 2020;77:108319.
|
[67] |
FuQ, NorthPE, KeX, et al. Adverse maternal environment and postweaning western diet alter hepatic CD36 expression and methylation concurrently with nonalcoholic fatty liver disease in mouse offspring. J Nutr. 2021;151(10):3102-3112.
|
[68] |
CuthbertCE, FosterJE, RamdathDD. A maternal high-fat, high-sucrose diet alters insulin sensitivity and expression of insulin signalling and lipid metabolism genes and proteins in male rat offspring: effect of folic acid supplementation. Br J Nutr. 2017;118(8):580-588.
|
[69] |
KnightAK, ParkHJ, HausmanDB, et al. Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood. Sci Rep. 2018;8(1):16873.
|
[70] |
YajnikCS, Deshmukh US. Fetal programming: maternal nutrition and role of one-carbon metabolism. Rev Endocr Metab Disord. 2012;13(2):121-127.
|
[71] |
KrishnaveniGV, VeenaSR, KaratSC, Yajnik CS, FallCH. Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia. 2014;57(1):110-121.
|
[72] |
HuangRF, HsuYC, LinHL, Yang FL. Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr. 2001;131(1):33-38.
|
[73] |
HuangY, HeY, SunX, HeY, LiY, SunC. Maternal high folic acid supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet. Int J Mol Sci. 2014;15(4):6298-6313.
|
[74] |
ChristensenKE, MikaelLG, LeungKY, et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015;101(3):646-658.
|
[75] |
TojalA, NevesC, VeigaH, et al. Perigestational high folic acid: impact on offspring's peripheral metabolic response. Food Funct. 2019;10(11):7216-7226.
|
[76] |
PaulL, SelhubJ. Interaction between excess folate and low vitamin B12 status. Mol Aspects Med. 2017;53:43-47.
|
[77] |
JiY, YinY, LiZ, ZhangW. Gut microbiota-derived components and metabolites in the progression of non-alcoholic fatty liver disease (NAFLD). Nutrients. 2019;11(8):1712.
|
[78] |
LeclercD, Jelinek J, ChristensenKE, IssaJJ, RozenR. High folic acid intake increases methylation-dependent expression of Lsr and dysregulates hepatic cholesterol homeostasis. J Nutr Biochem. 2021;88:108554.
|
[79] |
YangS, YeZ, LiuM, et al. Associations of different serum folate forms with indices of nonalcoholic fatty liver disease and advanced fibrosis. Obes Res Clin Pract. 2023;17(1):58-65.
|
[80] |
LyallMJ, Thomson JP, CartierJ, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with dynamic changes in DNA hydroxymethylation. Epigenetics. 2020;15(1-2):61-71.
|
[81] |
NiculescuMD, ZeiselSH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002;132:2333S-2335S.
|
[82] |
GopinathB, FloodVM, RochtchinaE, Wang JJ, MitchellP. Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. Am J Clin Nutr. 2013;98(1):129-135.
|
[83] |
ZhangJ, LiuTT, ZhangW, et al. Hyperhomocysteinemia is associated with vitamin B-12 deficiency: a cross-sectional study in a rural, elderly population of Shanxi, China. J Nutr Health Aging. 2016;20(6):594-601.
|
[84] |
JakubowskiH. Homocysteine modification in protein structure/function and human disease. Physiol Rev. 2019;99(1):555-604.
|
[85] |
AiY, SunZ, PengC, Liu L, XiaoX, LiJ. Homocysteine induces hepatic steatosis involving ER stress response in high methionine diet-fed mice. Nutrients. 2017;9(4):346.
|
[86] |
GallistlS, SudiKM, ErwaW, Aigner R, BorkensteinM. Determinants of homocysteine during weight reduction in obese children and adolescents. Metabolism. 2001;50(10):1220-1223.
|
[87] |
HerrmannW, Herrmann M. The controversial role of HCY and vitamin B deficiency in cardiovascular diseases. Nutrients. 2022;14(7):1412.
|
[88] |
LeachNV, DroncaE, VesaSC, et al. Serum homocysteine levels, oxidative stress and cardiovascular risk in non-alcoholic steatohepatitis. Eur J Intern Med. 2014;25(8):762-767.
|
[89] |
BalintB, Jepchumba VK, GuéantJL, Guéant-RodriguezRM. Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall. Biochimie. 2020;173:100-106.
|
[90] |
LebeaupinC, Vallée D, HazariY, HetzC, ChevetE, Bailly-MaitreB. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69(4):927-947.
|
[91] |
SchneiderMP, Schlaich MP, HaraznyJM, et al. Folic acid treatment normalizes NOS-dependence of vascular tone in the metabolic syndrome. Obesity. 2011;19(5):960-967.
|
[92] |
TripathiM, SinghBK, ZhouJ, et al. Vitamin B(12) and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation. J Hepatol. 2022;77(5):1246-1255.
|
[93] |
BagheriehM, Kheirollahi A, Zamani-GarmsiriF, EmamgholipourS, Meshkani R. Folic acid ameliorates palmitate-induced inflammation through decreasing homocysteine and inhibiting NF-κB pathway in HepG2 cells. Arch Physiol Biochem. 2021;129:1-8.
|
[94] |
Gallego-LopezM, OjedaML, Romero-HerreraI, NogalesF, Carreras O. Folic acid homeostasis and its pathways related to hepatic oxidation in adolescent rats exposed to binge drinking. Antioxidants. 2022;11(2):362.
|
[95] |
AbdulkhaleqFM, Alhussainy TM, BadrMM, et al. Antioxidative stress effects of vitamins C, E, and B(12), and their combination can protect the liver against acetaminophen-induced hepatotoxicity in rats. Drug Des Dev Ther. 2018;12:3525-3533.
|
[96] |
MajumdarS, MaitiA, KarmakarS, et al. Antiapoptotic efficacy of folic acid and vitamin B12 against arsenic-induced toxicity. Environ Toxicol. 2012;27(6):351-363.
|
[97] |
CanoMJ, AyalaA, MurilloML, Carreras O. Protective effect of folic acid against oxidative stress produced in 21-day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period. Free Radic Res. 2001;34(1):1-8.
|
[98] |
PogribnyIP, Tryndyak VP, MuskhelishviliL, RusynI, RossSA. Methyl deficiency, alterations in global histone modifications, and carcinogenesis. J Nutr. 2007;137:216S-222S.
|
[99] |
SmithAD, KimYI, RefsumH. Is folic acid good for everyone. Am J Clin Nutr. 2008;87(3):517-533.
|
[100] |
PogribnyIP, JamesSJ, BelandFA. Molecular alterations in hepatocarcinogenesis induced by dietary methyl deficiency. Mol Nutr Food Res. 2012;56(1):116-125.
|
[101] |
PerssonEC, Schwartz LM, ParkY, et al. Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality. Cancer Epidemiol Biomarkers Prev. 2013;22(3):415-421.
|
[102] |
SharmaR, AliT, NegiI, Das A, DusejaA, KaurJ. Dietary modulations of folic acid affect the development of diethylnitrosamine induced hepatocellular carcinoma in a rat model. J Mol Histol. 2021;52(2):335-350.
|
[103] |
MalaguarneraG, Catania VE, BertinoG, et al. Serum folate deficiency in HCV related hepatocellular carcinoma. Sci Rep. 2022;12(1):5025.
|
[104] |
MasonJB, TangSY. Folate status and colorectal cancer risk: a 2016 update. Mol Aspects Med. 2017;53:73-79.
|
[105] |
JiangY, HuangX, LiangP, et al. Low erythrocyte folate levels and increased risk of invasive cervical cancer in Chinese women. J Obstet Gynaecol Res. 2022;48(12):3191-3198.
|
[106] |
DaiWM, YangB, ChuXY, et al. Association between folate intake, serum folate levels and the risk of lung cancer: a systematic review and meta-analysis. Chin Med J. 2013;126(10):1957-1964.
|
[107] |
UhlenhoppDJ, ThenEO, SunkaraT, Gaduputi V. Epidemiology of esophageal cancer: update in global trends, etiology and risk factors. Clin J Gastroenterol. 2020;13(6):1010-1021.
|
[108] |
CuiLH, QuanZY, PiaoJM, et al. Plasma folate and vitamin B12 levels in patients with hepatocellular carcinoma. Int J Mol Sci. 2016;17(7):1032.
|
[109] |
KuoCS, LinCY, WuMY, LuCL, HuangRF. Relationship between folate status and tumour progression in patients with hepatocellular carcinoma. Br J Nutr. 2008;100(3):596-602.
|
[110] |
YehCC, GoyalA, ShenJ, et al. Global level of plasma DNA methylation is associated with overall survival in patients with hepatocellular carcinoma. Ann Surg Oncol. 2017;24(12):3788-3795.
|
[111] |
FangAP, LiuZY, LiaoGC, et al. Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong liver cancer cohort study. Br J Nutr. 2019;121(12):1376-1388.
|
[112] |
WuMT, YeWT, WangYC, et al. MTHFR knockdown assists cell defense against folate depletion induced chromosome segregation and uracil misincorporation in DNA. Int J Mol Sci. 2021;22(17):9392.
|
[113] |
JamesSJ, Pogribny IP, PogribnaM, MillerBJ, Jernigan S, MelnykS. Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J Nutr. 2003;133:3740S-3747S.
|
[114] |
ChernCL, HuangRF, ChenYH, Cheng JT, LiuTZ. Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-kappaB in human Hep G2 cells. Biomed Pharmacother. 2001;55(8):434-442.
|
[115] |
SuYH, HuangWC, HuangTH, et al. Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes. Oncotarget. 2016;7(22):33246-33256.
|
[116] |
FifeJ, RanigaS, HiderPN, Frizelle FA. Folic acid supplementation and colorectal cancer risk: a meta-analysis. Colorectal Dis. 2011;13(2):132-137.
|
[117] |
MarsillachJ, Ferré N, CampsJ, RiuF, RullA, JovenJ. Moderately high folic acid supplementation exacerbates experimentally induced liver fibrosis in rats. Exp Biol Med. 2008;233(1):38-47.
|
[118] |
LiJT, YangH, LeiMZ, et al. Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA. Signal Transduct Target Ther. 2022;7(1):192.
|
[119] |
FanJ, YeJ, KamphorstJJ, Shlomi T, ThompsonCB, RabinowitzJD. Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 2014;510(7504):298-302.
|
[120] |
SharmaR, AliT, KaurJ. Folic acid depletion as well as oversupplementation helps in the progression of hepatocarcinogenesis in HepG2 cells. Sci Rep. 2022;12(1):16617.
|
[121] |
GoyalH, SharmaR, LambaD, Kaur J. Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells. Mol Cell Biochem. 2023;478(9):2057-2068.
|
[122] |
NawazFZ, Kipreos ET. Emerging roles for folate receptor FOLR1 in signaling and cancer. Trends Endocrinol Metab. 2022;33(3):159-174.
|
[123] |
DilawariA, ShahM, IsonG, et al. FDA approval summary: mirvetuximab Soravtansine-Gynx for FRα-Positive, platinum-resistant ovarian cancer. Clin Cancer Res. 2023;29(19):3835-3840.
|
[124] |
JiaL, LiJ, LiP, et al. Site-specific glycoproteomic analysis revealing increased core-fucosylation on FOLR1 enhances folate uptake capacity of HCC cells to promote EMT. Theranostics. 2021;11(14):6905-6921.
|
[125] |
ZhuL, BakerSS, GillC, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57(2):601-609.
|
[126] |
BoursierJ, Mueller O, BarretM, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016;63(3):764-775.
|
[127] |
HuJ, GuoP, MaoR, et al. Gut microbiota signature of obese adults across different classifications. Diabetes Metab Syndr Obes. 2022;15:3933-3947.
|
[128] |
SafariZ, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci. 2019;76(8):1541-1558.
|
[129] |
MichailS, LinM, FreyMR, et al. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol. 2015;91(2):1-9.
|
[130] |
SmirnovaE, Muthiah MD, NarayanN, et al. Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD. Hepatology. 2022;76(6):1811-1824.
|
[131] |
DemirM, LangS, HartmannP, et al. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol. 2022;76(4):788-799.
|
[132] |
Le RoyT, LlopisM, LepageP, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62(12):1787-1794.
|
[133] |
KolodziejczykAA, ZhengD, ShiboletO, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Mol Med. 2019;11(2):e9302.
|
[134] |
GangarapuV, InceAT, BaysalB, et al. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2015;27(7):840-845.
|
[135] |
AleksandrovaK, Romero-Mosquera B, HernandezV. Diet, gut microbiome and epigenetics: emerging links with inflammatory bowel diseases and prospects for management and prevention. Nutrients. 2017;9(9):962.
|
[136] |
RatajczakAE, Szymczak-Tomczak A, RychterAM, ZawadaA, Dobrowolska A, Krela-Kaźmierczak I. Does folic acid protect patients with inflammatory bowel disease from complications. Nutrients. 2021;13(11):4036.
|
[137] |
WuJ, ZhaoY, WangX, et al. Dietary nutrients shape gut microbes and intestinal mucosa via epigenetic modifications. Crit Rev Food Sci Nutr. 2022;62(3):783-797.
|
[138] |
HanW, LiM, YangM, et al. Dietary folic acid supplementation inhibits high-fat diet-induced body weight gain through gut microbiota-associated branched-chain amino acids and mitochondria in mice. J Nutr Sci Vitaminol. 2023;69(2):105-120.
|
[139] |
KinoshitaM, KayamaH, KusuT, et al. Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. J Immunol. 2012;189(6):2869-2878.
|
[140] |
SamblasM, Martínez JA, MilagroF. Folic acid improves the inflammatory response in LPS-activated THP-1 macrophages. Mediators Inflamm. 2018;2018:1312626.
|
[141] |
ShulpekovaY, Nechaev V, KardashevaS, et al. The concept of folic acid in health and disease. Molecules. 2021;26(12):3731.
|
[142] |
AsrarFM, O'Connor DL. Bacterially synthesized folate and supplemental folic acid are absorbed across the large intestine of piglets. J Nutr Biochem. 2005;16(10):587-593.
|
[143] |
KimYR, HongSH. Associations of MTRR and TSER polymorphisms related to folate metabolism with susceptibility to metabolic syndrome. Genes Genomics. 2019;41(8):983-991.
|
[144] |
SugaharaH, Odamaki T, HashikuraN, AbeF, XiaoJZ. Differences in folate production by bifidobacteria of different origins. Biosci Microbiota Food Health. 2015;34(4):87-93.
|
[145] |
PompeiA, Cordisco L, AmarettiA, et al. Administration of folate-producing bifidobacteria enhances folate status in Wistar rats. J Nutr. 2007;137(12):2742-2746.
|
[146] |
ZhangJ, CaiD, YangM, et al. Screening of folate-producing lactic acid bacteria and modulatory effects of folate-biofortified yogurt on gut dysbacteriosis of folate-deficient rats. Food Funct. 2020;11(7):6308-6318.
|
[147] |
ValentiniL, PintoA, Bourdel-MarchassonI, et al. Impact of personalized diet and probiotic supplementation on inflammation, nutritional parameters and intestinal microbiota—the “RISTOMED project”: randomized controlled trial in healthy older people. Clin Nutr. 2015;34(4):593-602.
|
[148] |
JoseS, BhallaP, SuraishkumarGK. Oxidative stress decreases the redox ratio and folate content in the gut microbe, Enterococcus durans (MTCC 3031). Sci Rep. 2018;8(1):12138.
|
[149] |
MjaasethUN, NorrisJC, AardemaN, et al. Excess vitamins or imbalance of folic acid and choline in the gestational diet alter the gut microbiota and obesogenic effects in wistar rat offspring. Nutrients. 2021;13(12):4510.
|
[150] |
ChenJ, Vitetta L. Gut microbiota metabolites in NAFLD pathogenesis and therapeutic implications. Int J Mol Sci. 2020;21(15):4510.
|
[151] |
PiyathilakeCJ, BadigaS, HernandezA, Brill IK, JollyPE. The consumption of micronutrients in relation to calorie intake and risk of insulin resistance. Nutr Metab Cardiovasc Dis. 2022;32(6):1385-1391.
|
[152] |
WeiJ, WeiY, HuangM, Wang P, JiaS. Is metformin a possible treatment for diabetic neuropathy. J Diabetes. 2022;14(10):658-669.
|
[153] |
MahabirS, Ettinger S, JohnsonL, et al. Measures of adiposity and body fat distribution in relation to serum folate levels in postmenopausal women in a feeding study. Eur J Clin Nutr. 2008;62(5):644-650.
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