{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:08:09Z","timestamp":1791655689516,"version":"4.3.4"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Nutr"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alcohol-associated liver disease (AALD) is one of most common chronic liver diseases. Hepatic steatosis is the earliest stage in AALD pathological spectrum, reversible by alcohol abstinence. Untreated steatosis can progress to steatohepatitis, fibrosis and\/or cirrhosis. Considering the difficulties in achieving complete abstinence, challenges in disease reversal at advanced stages, high costs of AALD management and lack of standardised prescribed medications for treatment, it is essential to explore low-cost natural compounds that can target AALD at an early stage and halt or decelerate disease progression. Betaine is a non-hazardous naturally occurring nutrient. Here, we address the mechanisms of alcohol-induced hepatic steatosis, the role of betaine in reversing the effects i.e., its action against hepatic steatosis in animal models and humans, and the associated cellular and molecular processes. Accordingly, the review discusses how betaine restores the alcohol-induced reduction in methylation potential by elevating the levels of S-adenosylmethionine and methionine. It details how betaine reinstates alcohol-induced alterations in the expressions and\/or activities of protein phosphtase-2A, FOXO1, PPAR-\u03b1, AMPK, SREBP-1c, fatty acid synthase, diacylglycerol transferase-2, adiponectin and nitric oxide. Interrelationships between these factors in preventing de novo lipogenesis, reducing hepatic uptake of adipose-tissue-derived free fatty acids, promoting VLDL synthesis and secretion, and restoring \u03b2-oxidation of fatty acids to attenuate hepatic triglyceride accumulation are elaborated. Despite its therapeutic potential, very few clinical trials have examined betaine\u2019s effect on alcohol-induced hepatic lipid accumulation. This review will provide further confidence to conduct randomised control trials to enable maximum utilisation of betaine\u2019s remedial properties to treat alcohol-induced hepatic steatosis.<\/jats:p>","DOI":"10.1007\/s00394-021-02738-2","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T10:02:43Z","timestamp":1637748163000},"page":"1167-1176","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Betaine in ameliorating alcohol-induced hepatic steatosis"],"prefix":"10.1007","volume":"61","author":[{"given":"Aisha","family":"Rehman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0716-5081","authenticated-orcid":false,"given":"Kosha J.","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"2738_CR1","doi-asserted-by":"publisher","first-page":"521","DOI":"10.3748\/wjg.v25.i5.521","volume":"25","author":"KJ Mehta","year":"2019","unstructured":"Mehta KJ, Farnaud SJ, Sharp PA (2019) Iron and liver fibrosis: mechanistic and clinical aspects. World J Gastroenterol 25:521\u2013538. https:\/\/doi.org\/10.3748\/wjg.v25.i5.521","journal-title":"World J Gastroenterol"},{"key":"2738_CR2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.alcohol.2018.02.003","volume":"71","author":"JA Thompson","year":"2018","unstructured":"Thompson JA, Martinson N, Martinson M (2018) Mortality and costs associated with alcoholic hepatitis: a claims analysis of a commercially insured population. Alcohol Fayettev N 71:57\u201363. https:\/\/doi.org\/10.1016\/j.alcohol.2018.02.003","journal-title":"Alcohol Fayettev N"},{"key":"2738_CR3","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","volume":"70","author":"SK Asrani","year":"2019","unstructured":"Asrani SK, Devarbhavi H, Eaton J, Kamath PS (2019) Burden of liver diseases in the world. J Hepatol 70:151\u2013171. https:\/\/doi.org\/10.1016\/j.jhep.2018.09.014","journal-title":"J Hepatol"},{"key":"2738_CR4","doi-asserted-by":"publisher","first-page":"e316","DOI":"10.1016\/S2468-2667(20)30062-1","volume":"5","author":"J Julien","year":"2020","unstructured":"Julien J, Ayer T, Bethea ED et al (2020) Projected prevalence and mortality associated with alcohol-related liver disease in the USA, 2019\u201340: a modelling study. Lancet Public Health 5:e316\u2013e323. https:\/\/doi.org\/10.1016\/S2468-2667(20)30062-1","journal-title":"Lancet Public Health"},{"key":"2738_CR5","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/hep.30866","volume":"71","author":"DW Crabb","year":"2020","unstructured":"Crabb DW, Im GY, Szabo G et al (2020) Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American association for the study of liver diseases. Hepatology 71:306\u2013333. https:\/\/doi.org\/10.1002\/hep.30866","journal-title":"Hepatology"},{"key":"2738_CR6","doi-asserted-by":"publisher","first-page":"456","DOI":"10.3390\/biology10060456","volume":"10","author":"MK Arumugam","year":"2021","unstructured":"Arumugam MK, Paal MC, Donohue TM et al (2021) Beneficial effects of betaine: a comprehensive review. Biology 10:456. https:\/\/doi.org\/10.3390\/biology10060456","journal-title":"Biology"},{"key":"2738_CR7","doi-asserted-by":"publisher","first-page":"5225","DOI":"10.3892\/mmr.2017.7295","volume":"16","author":"W Yang","year":"2017","unstructured":"Yang W, Huang L, Gao J et al (2017) Betaine attenuates chronic alcohol-induced fatty liver by broadly regulating hepatic lipid metabolism. Mol Med Rep 16:5225\u20135234. https:\/\/doi.org\/10.3892\/mmr.2017.7295","journal-title":"Mol Med Rep"},{"key":"2738_CR8","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1111\/add.15329","volume":"116","author":"J Henssler","year":"2021","unstructured":"Henssler J, M\u00fcller M, Carreira H et al (2021) Controlled drinking\u2014non-abstinent versus abstinent treatment goals in alcohol use disorder: a systematic review, meta-analysis and meta-regression. Addiction 116:1973\u20131987. https:\/\/doi.org\/10.1111\/add.15329","journal-title":"Addiction"},{"key":"2738_CR9","doi-asserted-by":"publisher","first-page":"E34","DOI":"10.3390\/nu8010034","volume":"8","author":"D Rajdl","year":"2016","unstructured":"Rajdl D, Racek J, Trefil L et al (2016) Effect of folic acid, betaine, vitamin B6, and vitamin B12 on homocysteine and dimethylglycine levels in middle-aged men drinking white wine. Nutrients 8:E34. https:\/\/doi.org\/10.3390\/nu8010034","journal-title":"Nutrients"},{"key":"2738_CR10","first-page":"147","volume":"38","author":"NA Osna","year":"2017","unstructured":"Osna NA, Donohue TM, Kharbanda KK (2017) Alcoholic liver disease: pathogenesis and current management. Alcohol Res Curr Rev 38:147\u2013161","journal-title":"Alcohol Res Curr Rev"},{"key":"2738_CR11","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1016\/j.bbagen.2016.02.001","volume":"1860","author":"CR Day","year":"2016","unstructured":"Day CR, Kempson SA (2016) Betaine chemistry, roles, and potential use in liver disease. Biochim Biophys Acta BBA-Gen Subj 1860:1098\u20131106. https:\/\/doi.org\/10.1016\/j.bbagen.2016.02.001","journal-title":"Biochim Biophys Acta BBA-Gen Subj"},{"key":"2738_CR12","first-page":"3","volume-title":"Food and nutritional components in focus","author":"VB Patel","year":"2015","unstructured":"Patel VB, Mehta K (2015) CHAPTER 1. Betaine in context. In: Preedy VR (ed) Food and nutritional components in focus. Royal Society of Chemistry, Cambridge, pp 3\u20138"},{"key":"2738_CR13","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1007\/s10620-006-8038-3","volume":"51","author":"K Samara","year":"2006","unstructured":"Samara K, Liu C, Soldevila-Pico C et al (2006) Betaine resolves severe alcohol-induced hepatitis and steatosis following liver transplantation. Dig Dis Sci 51:1226\u20131229. https:\/\/doi.org\/10.1007\/s10620-006-8038-3","journal-title":"Dig Dis Sci"},{"key":"2738_CR14","doi-asserted-by":"publisher","first-page":"803.8","DOI":"10.1096\/fasebj.31.1_supplement.803.8","volume":"31","author":"DS Jun","year":"2017","unstructured":"Jun DS, Choi YJ, Ahn CW, Kim YC (2017) Acceleration of liver regeneration by betaine supplementation after partial hepatectomy. FASEB J 31:803.8-803.8. https:\/\/doi.org\/10.1096\/fasebj.31.1_supplement.803.8","journal-title":"FASEB J"},{"key":"2738_CR15","doi-asserted-by":"publisher","first-page":"5745","DOI":"10.3748\/wjg.v26.i38.5745","volume":"26","author":"S Mukherjee","year":"2020","unstructured":"Mukherjee S (2020) Role of betaine in liver disease-worth revisiting or has the die been cast? World J Gastroenterol 26:5745\u20135748. https:\/\/doi.org\/10.3748\/wjg.v26.i38.5745","journal-title":"World J Gastroenterol"},{"key":"2738_CR16","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13023-019-1036-2","volume":"14","author":"V Valayannopoulos","year":"2019","unstructured":"Valayannopoulos V, Schiff M, Guffon N et al (2019) Betaine anhydrous in homocystinuria: results from the RoCH registry. Orphanet J Rare Dis 14:66. https:\/\/doi.org\/10.1186\/s13023-019-1036-2","journal-title":"Orphanet J Rare Dis"},{"key":"2738_CR17","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.biopha.2018.04.010","volume":"103","author":"R Heidari","year":"2018","unstructured":"Heidari R, Niknahad H, Sadeghi A et al (2018) Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury. Biomed Pharmacother 103:75\u201386. https:\/\/doi.org\/10.1016\/j.biopha.2018.04.010","journal-title":"Biomed Pharmacother"},{"key":"2738_CR18","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1097\/MPA.0000000000000557","volume":"45","author":"W Yang","year":"2016","unstructured":"Yang W, Gao J, Tai Y et al (2016) Betaine attenuates alcohol-induced pancreatic steatosis. Pancreas 45:836\u2013845. https:\/\/doi.org\/10.1097\/MPA.0000000000000557","journal-title":"Pancreas"},{"key":"2738_CR19","doi-asserted-by":"publisher","first-page":"3198","DOI":"10.1007\/s10620-013-2775-x","volume":"58","author":"W Zhang","year":"2013","unstructured":"Zhang W, Wang L-W, Wang L-K et al (2013) Betaine protects against high-fat-diet-induced liver injury by inhibition of high-mobility group box 1 and Toll-like receptor 4 expression in rats. Dig Dis Sci 58:3198\u20133206. https:\/\/doi.org\/10.1007\/s10620-013-2775-x","journal-title":"Dig Dis Sci"},{"key":"2738_CR20","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1093\/ajcn\/80.3.539","volume":"80","author":"SA Craig","year":"2004","unstructured":"Craig SA (2004) Betaine in human nutrition. Am J Clin Nutr 80:539\u2013549. https:\/\/doi.org\/10.1093\/ajcn\/80.3.539","journal-title":"Am J Clin Nutr"},{"key":"2738_CR21","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1078\/0940-2993-00347","volume":"55","author":"J Balkan","year":"2004","unstructured":"Balkan J, \u00d6ztezcan S, K\u00fc\u00e7\u00fck M et al (2004) The effect of betaine treatment on triglyceride levels and oxidative stress in the liver of ethanol-treated guinea pigs. Exp Toxicol Pathol 55:505\u2013509. https:\/\/doi.org\/10.1078\/0940-2993-00347","journal-title":"Exp Toxicol Pathol"},{"key":"2738_CR22","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1093\/ajcn\/86.1.14","volume":"86","author":"V Purohit","year":"2007","unstructured":"Purohit V, Abdelmalek MF, Barve S et al (2007) Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr 86:14\u201324. https:\/\/doi.org\/10.1093\/ajcn\/86.1.14","journal-title":"Am J Clin Nutr"},{"key":"2738_CR23","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/962183","volume":"2012","author":"KK Kharbanda","year":"2012","unstructured":"Kharbanda KK, Todero SL, King AL et al (2012) Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome. Int J Hepatol 2012:962183. https:\/\/doi.org\/10.1155\/2012\/962183","journal-title":"Int J Hepatol"},{"key":"2738_CR24","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1039\/c8fo02004c","volume":"10","author":"L Zhang","year":"2019","unstructured":"Zhang L, Qi Y, ALuo Z, et al (2019) Betaine increases mitochondrial content and improves hepatic lipid metabolism. Food Funct 10:216\u2013223. https:\/\/doi.org\/10.1039\/c8fo02004c","journal-title":"Food Funct"},{"key":"2738_CR25","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112712","author":"L-Z Kong","year":"2019","unstructured":"Kong L-Z, Chandimali N, Han Y-H et al (2019) Pathogenesis, early diagnosis, and therapeutic management of alcoholic liver disease. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms20112712","journal-title":"Int J Mol Sci"},{"key":"2738_CR26","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1159\/000356622","volume":"32","author":"SA Kempson","year":"2013","unstructured":"Kempson SA, Vovor-Dassu K, Day C (2013) Betaine transport in kidney and liver: use of betaine in liver injury. Cell Physiol Biochem 32:32\u201340. https:\/\/doi.org\/10.1159\/000356622","journal-title":"Cell Physiol Biochem"},{"key":"2738_CR27","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.bbrc.2016.06.080","volume":"477","author":"CW Ahn","year":"2016","unstructured":"Ahn CW, Jun DS, Na JD et al (2016) Alleviation of hepatic fat accumulation by betaine involves reduction of homocysteine via up-regulation of betaine-homocysteine methyltransferase (BHMT). Biochem Biophys Res Commun 477:440\u2013447. https:\/\/doi.org\/10.1016\/j.bbrc.2016.06.080","journal-title":"Biochem Biophys Res Commun"},{"key":"2738_CR28","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.jhep.2006.08.024","volume":"46","author":"KK Kharbanda","year":"2007","unstructured":"Kharbanda KK, Mailliard ME, Baldwin CR et al (2007) Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. J Hepatol 46:314\u2013321. https:\/\/doi.org\/10.1016\/j.jhep.2006.08.024","journal-title":"J Hepatol"},{"key":"2738_CR29","doi-asserted-by":"publisher","first-page":"3481","DOI":"10.3390\/nu5093481","volume":"5","author":"R Obeid","year":"2013","unstructured":"Obeid R (2013) The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients 5:3481\u20133495. https:\/\/doi.org\/10.3390\/nu5093481","journal-title":"Nutrients"},{"key":"2738_CR30","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.yexmp.2015.03.007","volume":"98","author":"S French","year":"2015","unstructured":"French S (2015) How to prevent alcoholic liver disase. Exp Mol Pathol 98:304\u2013307. https:\/\/doi.org\/10.1016\/j.yexmp.2015.03.007","journal-title":"Exp Mol Pathol"},{"key":"2738_CR31","doi-asserted-by":"publisher","first-page":"4073","DOI":"10.1111\/bph.12765","volume":"171","author":"X Dou","year":"2014","unstructured":"Dou X, Xia Y, Chen J et al (2014) Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease. Br J Pharmacol 171:4073\u20134086. https:\/\/doi.org\/10.1111\/bph.12765","journal-title":"Br J Pharmacol"},{"key":"2738_CR32","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.alcohol.2004.07.004","volume":"34","author":"M You","year":"2004","unstructured":"You M, Crabb DW (2004) Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. Alcohol Fayettev N 34:39\u201343. https:\/\/doi.org\/10.1016\/j.alcohol.2004.07.004","journal-title":"Alcohol Fayettev N"},{"key":"2738_CR33","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3390\/biom6030029","volume":"6","author":"RA Ansari","year":"2016","unstructured":"Ansari RA, Husain K, Rizvi SAA (2016) Role of transcription factors in steatohepatitis and hypertension after ethanol: the epicenter of metabolism. Biomolecules 6:29. https:\/\/doi.org\/10.3390\/biom6030029","journal-title":"Biomolecules"},{"key":"2738_CR34","doi-asserted-by":"publisher","first-page":"G894","DOI":"10.1152\/ajpgi.00133.2007","volume":"293","author":"Z Song","year":"2007","unstructured":"Song Z, Deaciuc I, Zhou Z et al (2007) Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. Am J Physiol Gastrointest Liver Physiol 293:G894\u2013G902. https:\/\/doi.org\/10.1152\/ajpgi.00133.2007","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2738_CR35","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1074\/jbc.M412107200","volume":"280","author":"C Am\u00e9en","year":"2005","unstructured":"Am\u00e9en C, Edvardsson U, Ljungberg A et al (2005) Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver. J Biol Chem 280:1224\u20131229. https:\/\/doi.org\/10.1074\/jbc.M412107200","journal-title":"J Biol Chem"},{"key":"2738_CR36","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1476-511X-12-34","volume":"12","author":"L Wang","year":"2013","unstructured":"Wang L, Chen L, Tan Y et al (2013) Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter. Lipids Health Dis 12:34. https:\/\/doi.org\/10.1186\/1476-511X-12-34","journal-title":"Lipids Health Dis"},{"key":"2738_CR37","doi-asserted-by":"publisher","first-page":"G1173","DOI":"10.1152\/ajpgi.90349.2008","volume":"295","author":"S Liangpunsakul","year":"2008","unstructured":"Liangpunsakul S, Wou S-E, Zeng Y et al (2008) Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation. Am J Physiol-Gastrointest Liver Physiol 295:G1173\u2013G1181. https:\/\/doi.org\/10.1152\/ajpgi.90349.2008","journal-title":"Am J Physiol-Gastrointest Liver Physiol"},{"key":"2738_CR38","doi-asserted-by":"publisher","first-page":"2490","DOI":"10.1194\/jlr.R025882","volume":"53","author":"RAK Srivastava","year":"2012","unstructured":"Srivastava RAK, Pinkosky SL, Filippov S et al (2012) AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res 53:2490\u20132514. https:\/\/doi.org\/10.1194\/jlr.R025882","journal-title":"J Lipid Res"},{"key":"2738_CR39","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3858\/emm.2010.42.3.021","volume":"42","author":"L Chen","year":"2010","unstructured":"Chen L, Wang F, Sun X et al (2010) Chronic ethanol feeding impairs AMPK and MEF2 expression and is associated with GLUT4 decrease in rat myocardium. Exp Mol Med 42:205\u2013215. https:\/\/doi.org\/10.3858\/emm.2010.42.3.021","journal-title":"Exp Mol Med"},{"key":"2738_CR40","doi-asserted-by":"publisher","first-page":"G1004","DOI":"10.1152\/ajpgi.00482.2009","volume":"298","author":"S Liangpunsakul","year":"2010","unstructured":"Liangpunsakul S, Sozio MS, Shin E et al (2010) Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels. Am J Physiol Gastrointest Liver Physiol 298:G1004-1012. https:\/\/doi.org\/10.1152\/ajpgi.00482.2009","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2738_CR41","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.jhep.2018.10.037","volume":"70","author":"M You","year":"2019","unstructured":"You M, Arteel GE (2019) Effect of ethanol on lipid metabolism. J Hepatol 70:237\u2013248. https:\/\/doi.org\/10.1016\/j.jhep.2018.10.037","journal-title":"J Hepatol"},{"key":"2738_CR42","doi-asserted-by":"publisher","first-page":"145","DOI":"10.2174\/157488407780598135","volume":"2","author":"X Deng","year":"2007","unstructured":"Deng X, Deitrich RA (2007) Ethanol metabolism and effects: nitric oxide and its interaction. Curr Clin Pharmacol 2:145\u2013153","journal-title":"Curr Clin Pharmacol"},{"key":"2738_CR43","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s11010-009-0044-2","volume":"327","author":"KK Kharbanda","year":"2009","unstructured":"Kharbanda KK, Todero SL, Ward BW et al (2009) Betaine administration corrects ethanol-induced defective VLDL secretion. Mol Cell Biochem 327:75\u201378. https:\/\/doi.org\/10.1007\/s11010-009-0044-2","journal-title":"Mol Cell Biochem"},{"key":"2738_CR44","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1042\/BJ20051966","volume":"395","author":"JD Sparks","year":"2006","unstructured":"Sparks JD, Collins HL, Chirieac DV et al (2006) Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine\u2013homocysteine S-methyltransferase. Biochem J 395:363\u2013371. https:\/\/doi.org\/10.1042\/BJ20051966","journal-title":"Biochem J"},{"key":"2738_CR45","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.toxlet.2020.05.035","volume":"331","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Yuan T, Su Z et al (2020) Reduced methylation of PP2Ac promotes ethanol-induced lipid accumulation through FOXO1 phosphorylation in vitro and in vivo. Toxicol Lett 331:65\u201374. https:\/\/doi.org\/10.1016\/j.toxlet.2020.05.035","journal-title":"Toxicol Lett"},{"key":"2738_CR46","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.plipres.2017.04.002","volume":"66","author":"Y Li","year":"2017","unstructured":"Li Y, Ma Z, Jiang S et al (2017) A global perspective on FOXO1 in lipid metabolism and lipid-related diseases. Prog Lipid Res 66:42\u201349. https:\/\/doi.org\/10.1016\/j.plipres.2017.04.002","journal-title":"Prog Lipid Res"},{"key":"2738_CR47","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1097\/MOL.0b013e32832b3f4c","volume":"20","author":"JD Sparks","year":"2009","unstructured":"Sparks JD, Dong HH (2009) FoxO1 and hepatic lipid metabolism. Curr Opin Lipidol 20:217\u2013226. https:\/\/doi.org\/10.1097\/MOL.0b013e32832b3f4c","journal-title":"Curr Opin Lipidol"},{"key":"2738_CR48","doi-asserted-by":"publisher","first-page":"20132","DOI":"10.1074\/jbc.M112.347211","volume":"287","author":"X Deng","year":"2012","unstructured":"Deng X, Zhang W, O-Sullivan I et al (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287:20132\u201320143. https:\/\/doi.org\/10.1074\/jbc.M112.347211","journal-title":"J Biol Chem"},{"key":"2738_CR49","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.molcel.2010.12.030","volume":"41","author":"V Stanevich","year":"2011","unstructured":"Stanevich V, Jiang L, Satyshur KA et al (2011) The structural basis for tight control of PP2A methylation and function by LCMT-1. Mol Cell 41:331\u2013342. https:\/\/doi.org\/10.1016\/j.molcel.2010.12.030","journal-title":"Mol Cell"},{"key":"2738_CR50","doi-asserted-by":"publisher","DOI":"10.2903\/j.efsa.2017.5057","volume":"15","author":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck D, Bresson J-L, et al","year":"2017","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck D, Bresson J-L, et al (2017) Safety of betaine as a novel food pursuant to regulation (EC) No 258\/97. EFSA J 15:e05057. https:\/\/doi.org\/10.2903\/j.efsa.2017.5057","journal-title":"EFSA J"},{"key":"2738_CR51","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1093\/jn\/136.1.34","volume":"136","author":"U Schwab","year":"2006","unstructured":"Schwab U, T\u00f6rr\u00f6nen A, Meririnne E et al (2006) Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. J Nutr 136:34\u201338. https:\/\/doi.org\/10.1093\/jn\/136.1.34","journal-title":"J Nutr"},{"key":"2738_CR52","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1002\/hep.23239","volume":"50","author":"MF Abdelmalek","year":"2009","unstructured":"Abdelmalek MF, Sanderson SO, Angulo P et al (2009) Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatol Baltim Md 50:1818\u20131826. https:\/\/doi.org\/10.1002\/hep.23239","journal-title":"Hepatol Baltim Md"},{"key":"2738_CR53","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1055\/s-0031-1300279","volume":"50","author":"F Miglio","year":"2000","unstructured":"Miglio F, Rovati LC, Santoro A, Setnikar I (2000) Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung 50:722\u2013727. https:\/\/doi.org\/10.1055\/s-0031-1300279","journal-title":"Arzneimittelforschung"},{"key":"2738_CR54","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.1111\/j.1572-0241.2001.04129.x","volume":"96","author":"MF Abdelmalek","year":"2001","unstructured":"Abdelmalek MF, Angulo P, Jorgensen RA et al (2001) Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 96:2711\u20132717. https:\/\/doi.org\/10.1111\/j.1572-0241.2001.04129.x","journal-title":"Am J Gastroenterol"},{"key":"2738_CR55","doi-asserted-by":"publisher","DOI":"10.2174\/1876399501103010001","author":"S Mukherjee","year":"2011","unstructured":"Mukherjee S, Bernard T, Kharbanda K et al (2011) Impact of betaine on hepatic fibrosis and homocysteine in nonalcoholic steatohepatitis\u2014a prospective. Cohort Study Open Transl Med J. https:\/\/doi.org\/10.2174\/1876399501103010001","journal-title":"Cohort Study Open Transl Med J"},{"key":"2738_CR56","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.yexmp.2011.02.006","volume":"90","author":"J Oliva","year":"2011","unstructured":"Oliva J, Bardag-Gorce F, Tillman B, French SW (2011) Protective effect of quercetin, egcg, catechin and betaine against oxidative stress induced by ethanol in vitro. Exp Mol Pathol 90:295\u2013299. https:\/\/doi.org\/10.1016\/j.yexmp.2011.02.006","journal-title":"Exp Mol Pathol"},{"key":"2738_CR57","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.yexmp.2011.10.001","volume":"92","author":"J Oliva","year":"2012","unstructured":"Oliva J, Zhong J, Buslon VS, French SW (2012) The effect of same and betaine on hepa 1\u20136, c34 and e47 liver cell survival in vitro. Exp Mol Pathol 92:126\u2013130. https:\/\/doi.org\/10.1016\/j.yexmp.2011.10.001","journal-title":"Exp Mol Pathol"},{"key":"2738_CR58","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2020.109129","volume":"325","author":"Z Hong","year":"2020","unstructured":"Hong Z, Lin M, Zhang Y et al (2020) Role of betaine in inhibiting the induction of RNA Pol III gene transcription and cell growth caused by alcohol. Chem Biol Interact 325:109129. https:\/\/doi.org\/10.1016\/j.cbi.2020.109129","journal-title":"Chem Biol Interact"},{"key":"2738_CR59","doi-asserted-by":"publisher","first-page":"21850","DOI":"10.1038\/s41598-020-78935-6","volume":"10","author":"Q Chen","year":"2020","unstructured":"Chen Q, Wang Y, Jiao F et al (2020) Betaine inhibits Toll-like receptor 4 responses and restores intestinal microbiota in acute liver failure mice. Sci Rep 10:21850. https:\/\/doi.org\/10.1038\/s41598-020-78935-6","journal-title":"Sci Rep"}],"container-title":["European Journal of Nutrition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00394-021-02738-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00394-021-02738-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00394-021-02738-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T16:16:26Z","timestamp":1647274586000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00394-021-02738-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,24]]},"references-count":59,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["2738"],"URL":"https:\/\/doi.org\/10.1007\/s00394-021-02738-2","relation":{},"ISSN":["1436-6207","1436-6215"],"issn-type":[{"value":"1436-6207","type":"print"},{"value":"1436-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,24]]},"assertion":[{"value":"7 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}