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Effects of betaine on non-alcoholic liver disease

Published online by Cambridge University Press:  05 April 2021

Weiqiang Chen ,
Minjuan Xu ,
Minwen Xu ,
Yucai Wang ,
Qingyan Zou ,
Shuixiang Xie  and
Liefeng Wang
Weiqiang Chen
Affiliation:
Guangzhou Kingmed Diagnostics Group Co., Ltd., Guangzhou, 510320, China Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, China
Minjuan Xu
Affiliation:
Department of Obstetrics and Gynecology, Ganzhou People’s Hospital, Ganzhou, 341000, China
Minwen Xu
Affiliation:
First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
Yucai Wang
Affiliation:
First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
Qingyan Zou
Affiliation:
First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
Shuixiang Xie*
Affiliation:
Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, China
Liefeng Wang*
Affiliation:
Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, China
*
*Correspondence authors: Shuixiang Xie, email xsxw2002@163.com and Liefeng Wang 469730795@qq.com
*Correspondence authors: Shuixiang Xie, email xsxw2002@163.com and Liefeng Wang 469730795@qq.com
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Abstract

The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) poses a growing challenge in terms of its prevention and treatment. The ‘multiple hits’ hypothesis of multiple insults, such as dietary fat intake, de novo lipogenesis, insulin resistance, oxidative stress, mitochondrial dysfunction, gut dysbiosis and hepatic inflammation, can provide a more accurate explanation of the pathogenesis of NAFLD. Betaine plays important roles in regulating the genes associated with NAFLD through anti-inflammatory effects, increased free fatty oxidation, anti-lipogenic effects and improved insulin resistance and mitochondrial function; however, the mechanism of betaine remains elusive.

Keywords

BetaineNAFLDAMPK
Type
Review Article
Information
Nutrition Research Reviews , Volume 35 , Issue 1 , June 2022 , pp. 28 - 38
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Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of The Nutrition Society

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Footnotes

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These authors contributed equally to this work.

References

Younossi, Z, Anstee, QM, Marietti, M, Hardy, T, Henry, L, Eslam, M, George, J, Bugianesi, E (2018) Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15 (1):11–20. doi: 10.1038/nrgastro.2017.109 CrossRefGoogle ScholarPubMed
Berlanga, A, Guiu-Jurado, E, Porras, JA, Auguet, T (2014) Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol 7:221–239. doi: 10.2147/ceg.s62831 Google ScholarPubMed
Tilg, H, Moschen, AR, Roden, M (2017) NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 14 (1):32–42. doi: 10.1038/nrgastro.2016.147 CrossRefGoogle ScholarPubMed
Samuel, VT, Shulman, GI (2018) Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 27 (1):22–41. doi: 10.1016/j.cmet.2017.08.002 CrossRefGoogle ScholarPubMed
Tilg, H, Moschen, AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52 (5):1836–1846. doi: 10.1002/hep.24001 CrossRefGoogle Scholar
Buzzetti, E, Pinzani, M, Tsochatzis, EA (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65 (8):1038–1048. doi: 10.1016/j.metabol.2015.12.012 CrossRefGoogle Scholar
Fabbrini, E, Mohammed, BS, Magkos, F, Korenblat, KM, Patterson, BW, Klein, S (2008) Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134 (2):424–431. doi: 10.1053/j.gastro.2007.11.038 CrossRefGoogle ScholarPubMed
Mantovani, A, Zaza, G, Byrne, CD, Lonardo, A, Zoppini, G, Bonora, E, Targher, G (2018) Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis. Metabolism 79:64–76. doi: 10.1016/j.metabol.2017.11.003 CrossRefGoogle ScholarPubMed
Lonardo, A, Nascimbeni, F, Mantovani, A, Targher, G (2018) Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol 68 (2):335–352. doi: 10.1016/j.jhep.2017.09.021 CrossRefGoogle ScholarPubMed
Rinella, ME (2015) Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22):2263–2273. doi: 10.1001/jama.2015.5370 CrossRefGoogle ScholarPubMed
Sookoian, S, Puri, P, Castaño, GO, Scian, R, Mirshahi, F, Sanyal, AJ, Pirola, CJ (2017) Nonalcoholic steatohepatitis is associated with a state of betaine-insufficiency. Liver Int 37 (4):611–619. doi: 10.1111/liv.13249 CrossRefGoogle ScholarPubMed
Du, J, Shen, L, Tan, Z, Zhang, P, Zhao, X, Xu, Y, Gan, M, Yang, Q, Ma, J, Jiang, Aa, Tang, G, Jiang, Y, Jin, L, Li, M, Bai, L, Li, X, Wang, J, Zhang, S, Zhu, L (2018) Betaine supplementation enhances lipid metabolism and improves insulin resistance in mice fed a high-fat diet. Nutrients 10 (2):131. doi: 10.3390/nu10020131 CrossRefGoogle ScholarPubMed
Veskovic, M, Mladenovic, D, Milenkovic, M, Tosic, J, Borozan, S, Gopcevic, K, Labudovic-Borovic, M, Dragutinovic, V, Vucevic, D, Jorgacevic, B, Isakovic, A, Trajkovic, V, Radosavljevic, T (2019) Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease. Eur J Pharmacol 848:39–48. doi: 10.1016/j.ejphar.2019.01.043 CrossRefGoogle ScholarPubMed
Hwang, H.Y.; Sun, J.H.; Park, G.B.; Joo, S.T. Effects of dietary glycine betaine on blood characteristics and pork quality. J Muscle Foods 2010, 21, 87–101.CrossRefGoogle Scholar
Sivanesan, S, Taylor, A, Zhang, J, Bakovic, M (2018) Betaine and choline improve lipid homeostasis in obesity by participation in mitochondrial oxidative demethylation. Front Nutr 5:61–61. doi: 10.3389/fnut.2018.00061 CrossRefGoogle ScholarPubMed
Xu, L, Huang, D, Hu, Q, Wu, J, Wang, Y, Feng, J (2015) Betaine alleviates hepatic lipid accumulation via enhancing hepatic lipid export and fatty acid oxidation in rats fed with a high-fat diet. Br J Nutr 113 (12):1835–1843. doi: 10.1017/S0007114515001130 CrossRefGoogle ScholarPubMed
Song, Z, Deaciuc, I, Zhou, Z, Song, M, Chen, T, Hill, D, McClain, CJ (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 (4):G894–G902. doi: 10.1152/ajpgi.00133.2007 CrossRefGoogle ScholarPubMed
Ejaz, A, Martinez-Guino, L, Goldfine, AB, Ribas-Aulinas, F, De Nigris, V, Ribó, S, Gonzalez-Franquesa, A, Garcia-Roves, PM, Li, E, Dreyfuss, JM, Gall, W, Kim, JK, Bottiglieri, T, Villarroya, F, Gerszten, RE, Patti, M-E, Lerin, C (2016) Dietary betaine supplementation increases Fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice. Diabetes 65 (4):902–912. doi: 10.2337/db15-1094 CrossRefGoogle ScholarPubMed
Abdelmalek, MF, Sanderson, SO, Angulo, P, Soldevila-Pico, C, Liu, C, Peter, J, Keach, J, Cave, M, Chen, T, McClain, CJ, Lindor, KD (2009) Betaine for nonalcoholic fatty liver disease: Results of a randomized placebo-controlled trial. Hepatology 50 (6):1818–1826. doi: 10.1002/hep.23239 CrossRefGoogle ScholarPubMed
Woods, A, Williams, JR, Muckett, PJ, Mayer, FV, Liljevald, M, Bohlooly-Y, M, Carling, D (2017) Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep 18 (13):3043–3051. doi: 10.1016/j.celrep.2017.03.011 CrossRefGoogle ScholarPubMed
Chen, Q, Liu, M, Yu, H, Li, J, Wang, S, Zhang, Y, Qiu, F, Wang, T (2018) Scutellaria baicalensis regulates FFA metabolism to ameliorate NAFLD through the AMPK-mediated SREBP signaling pathway. J Nat Med 72 (3):655–666. doi: 10.1007/s11418-018-1199-5 CrossRefGoogle ScholarPubMed
Garcia, D, Hellberg, K, Chaix, A, Wallace, M, Herzig, S, Badur, MG, Lin, T, Shokhirev, MN, Pinto, AFM, Ross, DS, Saghatelian, A, Panda, S, Dow, LE, Metallo, CM, Shaw, RJ (2019) Genetic Liver-specific AMPK activation protects against diet-induced obesity and NAFLD. Cell Rep 26 (1):192–208.e196. doi: 10.1016/j.celrep.2018.12.036 CrossRefGoogle ScholarPubMed
Weikel, KA, Ruderman, NB, Cacicedo, JM (2016) Unraveling the actions of AMP-activated protein kinase in metabolic diseases: systemic to molecular insights. Metabolism 65 (5):634–645. doi: 10.1016/j.metabol.2016.01.005 CrossRefGoogle ScholarPubMed
Dahlhoff, C, Worsch, S, Sailer, M, Hummel, BA, Fiamoncini, J, Uebel, K, Obeid, R, Scherling, C, Geisel, J, Bader, BL, Daniel, H (2014) Methyl-donor supplementation in obese mice prevents the progression of NAFLD, activates AMPK and decreases acyl-carnitine levels. Mol Metab 3 (5):565–580. doi: 10.1016/j.molmet.2014.04.010 CrossRefGoogle ScholarPubMed
Deminice, R, Silva, R, Lamarre, S, Kelly, K, Jacobs, R, Brosnan, M, Brosnan, J (2015) Betaine supplementation prevents fatty liver induced by a high-fat diet: effects on one-carbon metabolism. Amino Acids 47. doi: 10.1007/s00726-014-1913-x CrossRefGoogle Scholar
Ma, J, Meng, X, Kang, SY, Zhang, J, Jung, HW, Park, Y-K (2019) Regulatory effects of the fruit extract of Lycium chinense and its active compound, betaine, on muscle differentiation and mitochondrial biogenesis in C2C12 cells. Biomed Pharmacother 118:109297. doi: 10.1016/j.biopha.2019.109297 CrossRefGoogle ScholarPubMed
Javary, J, Allain-Courtois, N, Saucisse, N, Costet, P, Heraud, C, Benhamed, F, Pierre, R, Bure, C, Pallares-Lupon, N, Do Cruzeiro, M, Postic, C, Cota, D, Dubus, P, Rosenbaum, J, Benhamouche-Trouillet, S (2018) Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling. Gut 67 (12):2192–2203. doi: 10.1136/gutjnl-2017-314208 CrossRefGoogle ScholarPubMed
Ahn, CW, Choi, YJ, Hong, SH, Jun, DS, Na, JD, Choi, YJ, Kim, YC (2015) Involvement of multiple pathways in the protection of liver against high-fat diet-induced steatosis by betaine. J Funct Foods 17:66–72. doi: 10.1016/j.jff.2015.05.010 CrossRefGoogle Scholar
Loh, K, Tam, S, Murray-Segal, L, Huynh, K, Meikle, PJ, Scott, JW, van Denderen, B, Chen, Z, Steel, R, LeBlond, ND, Burkovsky, LA, O’Dwyer, C, Nunes, JRC, Steinberg, GR, Fullerton, MD, Galic, S, Kemp, BE (2019) Inhibition of adenosine monophosphate-activated protein kinase-3-hydroxy-3-methylglutaryl coenzyme a reductase signaling leads to hypercholesterolemia and promotes hepatic steatosis and insulin resistance. Hepatol Commun 3 (1):84–98. doi: 10.1002/hep4.1279 CrossRefGoogle ScholarPubMed
Esquejo, RM, Salatto, CT, Delmore, J, Albuquerque, B, Reyes, A, Shi, Y, Moccia, R, Cokorinos, E, Peloquin, M, Monetti, M, Barricklow, J, Bollinger, E, Smith, BK, Day, EA, Nguyen, C, Geoghegan, KF, Kreeger, JM, Opsahl, A, Ward, J, Kalgutkar, AS, Tess, D, Butler, L, Shirai, N, Osborne, TF, Steinberg, GR, Birnbaum, MJ, Cameron, KO, Miller, RA (2018) Activation of liver AMPK with PF-06409577 corrects NAFLD and lowers cholesterol in rodent and primate preclinical models. EBioMedicine 31:122–132. doi: 10.1016/j.ebiom.2018.04.009 CrossRefGoogle ScholarPubMed
Maithilikarpagaselvi, N, Sridhar, MG, Swaminathan, RP, Sripradha, R, Badhe, B (2016) Curcumin inhibits hyperlipidemia and hepatic fat accumulation in high-fructose-fed male Wistar rats. Pharm Biol 54 (12):2857–2863. doi: 10.1080/13880209.2016.1187179 CrossRefGoogle ScholarPubMed
Sim, W-C, Kim, DG, Lee, KJ, Choi, Y-J, Choi, YJ, Shin, KJ, Jun, DW, Park, S-J, Park, H-J, Kim, J, Oh, WK, Lee, B-H (2015) Cinnamamides, novel liver X receptor antagonists that inhibit ligand-induced lipogenesis and fatty liver. J Pharmacol Exp Ther 355 (3):362–369. doi: 10.1124/jpet.115.226738 CrossRefGoogle ScholarPubMed
Cai, D, Yuan, M, Liu, H, Pan, S, Ma, W, Hong, J, Zhao, R (2016) Maternal betaine supplementation throughout gestation and lactation modifies hepatic cholesterol metabolic genes in weaning piglets via AMPK/LXR-mediated pathway and histone modification. Nutrients 8 (10):646 CrossRefGoogle ScholarPubMed
Lee, J, Hong, S-W, Park, SE, Rhee, E-J, Park, C-Y, Oh, K-W, Park, S-W, Lee, W-Y (2015) AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol 414:148–155. doi: 10.1016/j.mce.2015.07.031 CrossRefGoogle ScholarPubMed
Ipsen, DH, Lykkesfeldt, J, Tveden-Nyborg, P (2018) Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 75 (18):3313–3327. doi: 10.1007/s00018-018-2860-6 CrossRefGoogle ScholarPubMed
Joselit, Y, Nanobashvili, K, Jack-Roberts, C, Greenwald, E, Malysheva, OV, Caudill, MA, Saxena, A, Jiang, X (2018) Maternal betaine supplementation affects fetal growth and lipid metabolism of high-fat fed mice in a temporal-specific manner. Nutr Diabetes 8 (1):41. doi: 10.1038/s41387-018-0035-z CrossRefGoogle Scholar
Wang, L-j, Zhang, H-w, Zhou, J-y, Liu, Y, Yang, Y, Chen, X-l, Zhu, C-h, Zheng, R-d, Ling, W-h, Zhu, H-l (2014) Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet. J Nutr Biochem 25 (3):329–336. doi: 10.1016/j.jnutbio.2013.11.007 CrossRefGoogle ScholarPubMed
Geric, I, Tyurina, YY, Krysko, O, Krysko, DV, De Schryver, E, Kagan, VE, Van Veldhoven, PP, Baes, M, Verheijden, S (2018) Lipid homeostasis and inflammatory activation are disturbed in classically activated macrophages with peroxisomal β-oxidation deficiency. Immunology 153 (3):342–356. doi: 10.1111/imm.12844 CrossRefGoogle ScholarPubMed
Paradies, G, Paradies, V, Ruggiero, FM, Petrosillo, G (2014) Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease. World J Gastroenterol 20 (39):14205–14218. doi: 10.3748/wjg.v20.i39.14205 CrossRefGoogle ScholarPubMed
Zhou, R, Yazdi, AS, Menu, P, Tschopp, J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469 (7329):221–225. doi: 10.1038/nature09663 CrossRefGoogle ScholarPubMed
Knupp, J, Arvan, P, Chang, A (2019) Increased mitochondrial respiration promotes survival from endoplasmic reticulum stress. Cell Death Differ 26 (3):487–501. doi: 10.1038/s41418-018-0133-4 CrossRefGoogle ScholarPubMed
Adjoumani, J-JY, Wang, K, Zhou, M, Liu, W, Zhang, D (2017) Effect of dietary betaine on growth performance, antioxidant capacity and lipid metabolism in blunt snout bream fed a high-fat diet. Fish Physiol Biochem 43 (6):1733–1745. doi: 10.1007/s10695-017-0405-9 CrossRefGoogle ScholarPubMed
Heidari, R, Niknahad, H, Sadeghi, A, Mohammadi, H, Ghanbarinejad, V, Ommati, MM, Hosseini, A, Azarpira, N, Khodaei, F, Farshad, O, Rashidi, E, Siavashpour, A, Najibi, A, Ahmadi, A, Jamshidzadeh, A (2018) Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury. Biomed Pharmacother 103:75–86. doi: 10.1016/j.biopha.2018.04.010 CrossRefGoogle ScholarPubMed
Mansouri, A, Gattolliat, C-H, Asselah, T (2018) Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 155 (3):629–647. doi: 10.1053/j.gastro.2018.06.083 CrossRefGoogle ScholarPubMed
Du, J, Zhang, X, Han, J, Man, K, Zhang, Y, Chu, ESH, Nan, Y, Yu, J (2017) Pro-inflammatory CXCR3 impairs mitochondrial function in experimental non-alcoholic steatohepatitis. Theranostics 7 (17):4192–4203. doi: 10.7150/thno.21400 CrossRefGoogle ScholarPubMed
Hall, AR, Burke, N, Dongworth, RK, Hausenloy, DJ (2014) Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. Br J Pharmacol 171 (8):1890–1906. doi: 10.1111/bph.12516 CrossRefGoogle ScholarPubMed
Nasrallah, CM, Horvath, TL (2014) Mitochondrial dynamics in the central regulation of metabolism. Nat Rev Endocrinol 10 (11):650–658. doi: 10.1038/nrendo.2014.160 CrossRefGoogle ScholarPubMed
Lee, I (2015) Betaine is a positive regulator of mitochondrial respiration. Biochem Biophys Res Commun 456 (2):621–625. doi: 10.1016/j.bbrc.2014.12.005 CrossRefGoogle ScholarPubMed
Hoffman Nolan, J, Parker Benjamin, L, Chaudhuri, R, Fisher-Wellman Kelsey, H, Kleinert, M, Humphrey Sean, J, Yang, P, Holliday, M, Trefely, S, Fazakerley Daniel, J, Stöckli, J, Burchfield James, G, Jensen Thomas, E, Jothi, R, Kiens, B, Wojtaszewski Jørgen, FP, Richter Erik, A, James David, E (2015) Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab 22 (5):922–935. doi: 10.1016/j.cmet.2015.09.001 CrossRefGoogle Scholar
Marin, W (2020) A-kinase anchoring protein 1 (AKAP1) and its role in some cardiovascular diseases. J Mol Cell Cardiol 138:99–109. doi: 10.1016/j.yjmcc.2019.11.154 CrossRefGoogle ScholarPubMed
Toyama, EQ, Herzig, S, Courchet, J, Lewis, TL Jr., Losón, OC, Hellberg, K, Young, NP, Chen, H, Polleux, F, Chan, DC, Shaw, RJ (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351 (6270):275–281. doi: 10.1126/science.aab4138 CrossRefGoogle ScholarPubMed
Garcia, D, Shaw, RJ (2017) AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66 (6):789–800. doi: 10.1016/j.molcel.2017.05.032 CrossRefGoogle ScholarPubMed
Schrepfer, E, Scorrano, L (2016) Mitofusins, from mitochondria to metabolism. Mol Cell 61 (5):683–694. doi: 10.1016/j.molcel.2016.02.022 CrossRefGoogle ScholarPubMed
Chen, Z, Tao, S, Li, X, Yao, Q (2018) Resistin destroys mitochondrial biogenesis by inhibiting the PGC-1α/ NRF1/TFAM signaling pathway. Biochem Biophys Res Commun 504 (1):13–18. doi: 10.1016/j.bbrc.2018.08.027 CrossRefGoogle ScholarPubMed
Hu, Y, Sun, Q, Liu, J, Jia, Y, Cai, D, Idriss, AA, Omer, NA, Zhao, R (2017) In ovo injection of betaine alleviates corticosterone-induced fatty liver in chickens through epigenetic modifications. Sci Rep 7 (1):40251. doi: 10.1038/srep40251 CrossRefGoogle ScholarPubMed
Picca, A. & Lezza, A. M. Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: useful insights from aging and calorie restriction studies. Mitochondrion 25, 67–75, doi: 10.1016/j.mito.2015.10.001 (2015).CrossRefGoogle ScholarPubMed
Banerjee, J, Bruckbauer, A, Zemel, MB (2016) Activation of the AMPK/Sirt1 pathway by a leucine–metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans. Metabolism 65 (11):1679–1691. doi: 10.1016/j.metabol.2016.06.011 CrossRefGoogle ScholarPubMed
Zhang, Y, Li, L, Wang, Q, Zhan, S, Wang, L, Zhong, T, Guo, J, Zhang, H (2018) Fibroblast growth factor 21 induces lipolysis more efficiently than it suppresses lipogenesis in goat adipocytes. Cytotechnology 70 (5):1423–1433. doi: 10.1007/s10616-018-0237-1 CrossRefGoogle ScholarPubMed
Li, X, Gong, H, Yang, S, Yang, L, Fan, Y, Zhou, Y (2017) Pectic bee pollen polysaccharide from rosa rugosa alleviates diet-induced hepatic steatosis and insulin resistance via induction of AMPK/mTOR-mediated autophagy. Molecules 22 (5):699 CrossRefGoogle ScholarPubMed
Wu, WK, Zhang, L, Chan, MT (2018) Autophagy, NAFLD and NAFLD-Related HCC. In: Obesity, Fatty Liver and Liver Cancer. Springer, pp 127-138. https://doi.org/10.1007/978-981-10-8684-7_10 CrossRefGoogle Scholar
González-Rodríguez, Á, Mayoral, R, Agra, N, Valdecantos, MP, Pardo, V, Miquilena-Colina, ME, Vargas-Castrillón, J, Lo Iacono, O, Corazzari, M, Fimia, GM, Piacentini, M, Muntané, J, Boscá, L, García-Monzón, C, Martín-Sanz, P, Valverde, ÁM (2014) Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis 5 (4):e1179–e1179. doi: 10.1038/cddis.2014.162 CrossRefGoogle ScholarPubMed
Wang, C, Wang, H, Zhang, D, Luo, W, Liu, R, Xu, D, Diao, L, Liao, L, Liu, Z (2018) Phosphorylation of ULK1 affects autophagosome fusion and links chaperone-mediated autophagy to macroautophagy. Nat Commun 9 (1):3492. doi: 10.1038/s41467-018-05449-1 CrossRefGoogle ScholarPubMed
Kim, J, Kundu, M, Viollet, B, Guan, KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13 (2):132–141. doi: 10.1038/ncb2152 CrossRefGoogle ScholarPubMed
Celestini, V, Tezil, T (2018) Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy. 9 (2):231. doi: 10.1038/s41419-018-0336-0 CrossRefGoogle Scholar
Zhou, J, Liao, W, Yang, J, Ma, K, Li, X, Wang, Y, Wang, D, Wang, L, Zhang, Y, Yin, Y, Zhao, Y, Zhu, W-G (2012) FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway. Autophagy 8 (12):1712–1723. doi: 10.4161/auto.21830 CrossRefGoogle ScholarPubMed
Ejarque, M, Ceperuelo-Mallafré, V, Serena, C, Maymo-Masip, E, Duran, X, Díaz-Ramos, A, Millan-Scheiding, M, Núñez-Álvarez, Y, Núñez-Roa, C, Gama, P, Garcia-Roves, PM, Peinado, MA, Gimble, JM, Zorzano, A, Vendrell, J, Fernández-Veledo, S (2019) Adipose tissue mitochondrial dysfunction in human obesity is linked to a specific DNA methylation signature in adipose-derived stem cells. Int J Obesity 43 (6):1256–1268. doi: 10.1038/s41366-018-0219-6 CrossRefGoogle ScholarPubMed
Begriche, K, Massart, J, Robin, M-A, Bonnet, F, Fromenty, B (2013) Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 58 (4):1497–1507. doi: 10.1002/hep.26226 CrossRefGoogle ScholarPubMed
Mishra, M, Kowluru, RA (2019) DNA methylation – a potential source of mitochondria dna base mismatch in the development of diabetic retinopathy. Mol Neurobiol 56 (1):88–101. doi: 10.1007/s12035-018-1086-9 CrossRefGoogle ScholarPubMed
Yang, Z, Yang, HM, Gong, DQ, Rose, SP, Pirgozliev, V, Chen, XS, Wang, ZY (2018) Transcriptome analysis of hepatic gene expression and DNA methylation in methionine- and betaine-supplemented geese (Anser cygnoides domesticus). Poultry Sci 97 (10):3463–3477. doi: 10.3382/ps/pey242 CrossRefGoogle Scholar
Idriss, AA, Hu, Y, Sun, Q, Jia, L, Jia, Y, Omer, NA, Abobaker, H, Zhao, R (2016) Prenatal betaine exposure modulates hypothalamic expression of cholesterol metabolic genes in cockerels through modifications of DNA methylation. Poultry Sci 96 (6):1715–1724. doi: 10.3382/ps/pew437 CrossRefGoogle Scholar
Bravard, A, Lefai, E, Meugnier, E, Pesenti, S, Disse, E, Vouillarmet, J, Peretti, N, Rabasa-Lhoret, R, Laville, M, Vidal, H, Rieusset, J (2011) FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction. Diabetes 60 (1):258–268. doi: 10.2337/db10-0281 CrossRefGoogle ScholarPubMed
Guo, J, Ren, W, Li, X, Xi, G, Li, Y, Gao, L, Liu, J, Su, D (2018) Altering of FTO in the serum and livers of NAFLD patients: a correlation analysis. Int J Clin Exp Med 11:6046–6053 Google Scholar
Wu, W, Feng, J, Jiang, D, Zhou, X, Jiang, Q, Cai, M, Wang, X, Shan, T, Wang, Y (2017) AMPK regulates lipid accumulation in skeletal muscle cells through FTO-dependent demethylation of N6-methyladenosine. Sci Rep 7 (1):41606. doi: 10.1038/srep41606 CrossRefGoogle ScholarPubMed
Zhong, X, Yu, J, Frazier, K, Weng, X, Li, Y, Cham, CM, Dolan, K, Zhu, X, Hubert, N, Tao, Y, Lin, F, Martinez-Guryn, K, Huang, Y, Wang, T, Liu, J, He, C, Chang, EB, Leone, V (2018) Circadian clock regulation of hepatic lipid metabolism by modulation of m6A mRNA methylation. Cell Rep 25 (7):1816–1828.e1814. doi: 10.1016/j.celrep.2018.10.068 CrossRefGoogle ScholarPubMed
Chen, J, Zhou, X, Wu, W, Wang, X, Wang, Y (2015) FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice. J Physiol Biochem 71 (3):405–413. doi: 10.1007/s13105-015-0420-1 CrossRefGoogle ScholarPubMed
Zhou, X, Chen, J, Chen, J, Wu, W, Wang, X, Wang, Y (2015) The beneficial effects of betaine on dysfunctional adipose tissue and N6-methyladenosine mRNA methylation requires the AMP-activated protein kinase α1 subunit. J Nutr Biochem 26 (12):1678–1684. doi: 10.1016/j.jnutbio.2015.08.014 CrossRefGoogle ScholarPubMed
Zhao, N, Yang, S, Sun, B, Feng, Y, Zhao, R (2020) Maternal betaine protects rat offspring from glucocorticoid-induced activation of lipolytic genes in adipose tissue through modification of DNA methylation. Eur J Nutr 59 (4):1707–1716. doi: 10.1007/s00394-019-02025-1 CrossRefGoogle ScholarPubMed
Wang, L, Chen, L, Tan, Y, Wei, J, Chang, Y, Jin, T, Zhu, H (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 (1):34. doi: 10.1186/1476-511X-12-34 CrossRefGoogle ScholarPubMed
Ruppert, PMM, Park, J-G, Xu, X, Hur, KY, Lee, A-H, Kersten, S (2019) Transcriptional profiling of PPARα−/− and CREB3L3−/− livers reveals disparate regulation of hepatoproliferative and metabolic functions of PPARα. BMC Genomics 20 (1):199. doi: 10.1186/s12864-019-5563-y CrossRefGoogle ScholarPubMed
Fentz, J, Kjøbsted, R, Birk, JB, Jordy, AB, Jeppesen, J, Thorsen, K, Schjerling, P, Kiens, B, Jessen, N, Viollet, B, Wojtaszewski, JF (2015) AMPKα is critical for enhancing skeletal muscle fatty acid utilization during in vivo exercise in mice. FASEB journal : official publication of the Federation of Am Soc Exp Biol 29 (5):1725–1738. doi: 10.1096/fj.14-266650 Google ScholarPubMed
Xiao, Y, Wang, J, Yan, W, Zhou, K, Cao, Y, Cai, W (2017) p38α MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure. Cell Death Dis 8 (10):e3110–e3110. doi: 10.1038/cddis.2017.523 CrossRefGoogle ScholarPubMed
Osorio, JS, Jacometo, CB, Zhou, Z, Luchini, D, Cardoso, FC, Loor, JJ (2016) Hepatic global DNA and peroxisome proliferator-activated receptor alpha promoter methylation are altered in peripartal dairy cows fed rumen-protected methionine. J Dairy Sci 99 (1):234–244. doi: 10.3168/jds.2015-10157 CrossRefGoogle ScholarPubMed
Xia, Y, Chen, S, Zhu, G, Huang, R, Yin, Y, Ren, W (2018) Betaine inhibits interleukin-1β production and release: potential mechanisms. Front Immunol 9:2670. doi: 10.3389/fimmu.2018.02670 CrossRefGoogle ScholarPubMed
Dekker, MJ, Su, Q, Baker, C, Rutledge, AC, Adeli, K (2010) Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab 299 (5):E685–E694. doi: 10.1152/ajpendo.00283.2010 CrossRefGoogle ScholarPubMed
Pan, H, Guo, J, Su, Z (2014) Advances in understanding the interrelations between leptin resistance and obesity. Physiol Behav 130:157–169. doi: 10.1016/j.physbeh.2014.04.003 CrossRefGoogle ScholarPubMed
Yan, F, Dai, G, Zheng, X (2016) Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/db mice. J Nutr Biochem 36:68–80. doi: 10.1016/j.jnutbio.2016.07.004 CrossRefGoogle ScholarPubMed
Park, W-H, Pak, YK (2011) Insulin-dependent suppression of cholesterol 7α-hydroxlase is a possible link between glucose and cholesterol metabolisms. Exp Mol Med 43 (10):571–579. doi: 10.3858/emm.2011.43.10.064 CrossRefGoogle ScholarPubMed
Haeusler, RA, Hartil, K, Vaitheesvaran, B, Arrieta-Cruz, I, Knight, CM, Cook, JR, Kammoun, HL, Febbraio, MA, Gutierrez-Juarez, R, Kurland, IJ, Accili, D (2014) Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat Commun 5 (1):5190. doi: 10.1038/ncomms6190 CrossRefGoogle ScholarPubMed
Kim, DH, Lee, B, Kim, MJ, Park, MH, An, HJ, Lee, EK, Chung, KW, Park, JW, Yu, BP, Choi, JS, Chung, HY (2016) Molecular mechanism of betaine on hepatic lipid metabolism: inhibition of forkhead box O1 (FoxO1) binding to peroxisome proliferator-activated receptor gamma (PPARγ). J Agric Food Chem 64 (36):6819–6825. doi: 10.1021/acs.jafc.6b02644 CrossRefGoogle Scholar
Guo, W, Li, D, You, V, Li, W, Hu, B, Zhang, S, Miao, L, Xian, M, Zhu, Y, Shen, X (2019) Cystathionine γ-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis. FASEB J 33 (3):4212–4224. doi: 10.1096/fj.201801894R CrossRefGoogle ScholarPubMed
Bertrand, L, Ginion, A, Beauloye, C, Hebert, AD, Guigas, B, Hue, L, Vanoverschelde, JL (2006) AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B. Am J Physiol Heart Circ Physiol 291 (1):H239–250. doi: 10.1152/ajpheart.01269.2005 CrossRefGoogle Scholar
Zhou, J, Wan, J, Shu, XE, Mao, Y, Liu, X-M, Yuan, X, Zhang, X, Hess, ME, Brüning, JC, Qian, S-B (2018) N6-Methyladenosine guides mRNA alternative translation during integrated stress response. Mol Cell 69 (4):636–647.e637. doi: 10.1016/j.molcel.2018.01.019 CrossRefGoogle ScholarPubMed
Jin, M, Ande, A, Kumar, A, Kumar, S (2013) Regulation of cytochrome P450 2e1 expression by ethanol: role of oxidative stress-mediated pkc/jnk/sp1 pathway. Cell Death Dis 4 (3):e554–e554. doi: 10.1038/cddis.2013.78 CrossRefGoogle Scholar
Zhou, X, He, L, Zuo, S, Zhang, Y, Wan, D, Long, C, Huang, P, Wu, X, Wu, C, Liu, G, Yin, Y (2018) Serine prevented high-fat diet-induced oxidative stress by activating AMPK and epigenetically modulating the expression of glutathione synthesis-related genes. Biochim Biophys Acta - Mol Basis Dis 1864 (2):488–498. doi: 10.1016/j.bbadis.2017.11.009 CrossRefGoogle ScholarPubMed
Zhou, R, Yazdi, AS, Menu, P, Tschopp, J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469 (7329):221–225. doi: 10.1038/nature09663 CrossRefGoogle ScholarPubMed
Cheng, N, Chen, S, Liu, X, Zhao, H, Cao, W (2019) Impact of Schisandra chinensis bee pollen on nonalcoholic fatty liver disease and gut microbiota in high fat diet induced obese mice. Nutrients 11 (2). doi: 10.3390/nu11020346 CrossRefGoogle Scholar
Timofte, D, Toarba, C, Hogas, S, Covic, A, Ciobica, A, Chirita, R, Lefter, R, Arhire, L, Arcan, O, Alexinschi, O (2016) The relevance of oxidative stress status in type 2 diabetes and the chronic consumption of alcohol. Rom Biotechnol Lett 21 (1):11247 Google Scholar
Samuel Varman, T, Shulman Gerald, I (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148 (5):852–871. doi: 10.1016/j.cell.2012.02.017 CrossRefGoogle Scholar
Jian, T, Ao, X, Wu, Y, Lv, H, Ma, L, Zhao, L, Tong, B, Ren, B, Chen, J, Li, W (2017) Total sesquiterpene glycosides from Loquat (Eriobotrya japonica) leaf alleviate high-fat diet induced non-alcoholic fatty liver disease through cytochrome P450 2E1 inhibition. Biomed Pharmacother 91:229–237. doi: 10.1016/j.biopha.2017.04.056 CrossRefGoogle ScholarPubMed
Ge, C-X, Yu, R, Xu, M-X, Li, P-Q, Fan, C-Y, Li, J-M, Kong, L-D (2016) Betaine prevented fructose-induced NAFLD by regulating LXRα/PPARα pathway and alleviating ER stress in rats. Eur J Pharmacol 770:154–164. doi: 10.1016/j.ejphar.2015.11.043 CrossRefGoogle ScholarPubMed
Ye, J, Zhu, N, Sun, R, et al. Metformin inhibits chemokine expression through the AMPK/NF-κB signaling pathway[J]. J Interferon Cytokine Res, 2018,38(9):363–369.CrossRefGoogle Scholar
Zhang, J, Sun, Ys, Zhao, L, Chen, T, Fan, M, Jiao, H, Zhao, J, Wang, X, Li, F, Li, H, Lin, H (2019) SCFAs-induced GLP-1 secretion links the regulation of gut microbiome on hepatic lipogenesis in chickens. bioRxiv:549857. doi: 10.1101/549857 CrossRefGoogle Scholar
Nagpal, R, Wang, S, Ahmadi, S, Hayes, J, Gagliano, J, Subashchandrabose, S, Kitzman, DW, Becton, T, Read, R, Yadav, H (2018) Human-origin probiotic cocktail increases short-chain fatty acid production via modulation of mice and human gut microbiome. Sci Rep 8 (1):12649. doi: 10.1038/s41598-018-30114-4 CrossRefGoogle ScholarPubMed
He, X, Ji, G, Jia, W, Li, H (2016) Gut microbiota and nonalcoholic fatty liver disease: insights on mechanism and application of metabolomics. Int J Mol Sci 17 (3):300–300. doi: 10.3390/ijms17030300 CrossRefGoogle ScholarPubMed
Jiang, W, Wu, N, Wang, X, Chi, Y, Zhang, Y, Qiu, X, Hu, Y, Li, J, Liu, Y (2015) Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep 5 (1):8096. doi: 10.1038/srep08096 CrossRefGoogle ScholarPubMed
Yokota, A, Fukiya, S, Islam, KBMS, Ooka, T, Ogura, Y, Hayashi, T, Hagio, M, Ishizuka, S (2012) Is bile acid a determinant of the gut microbiota on a high-fat diet? Gut Microbes 3 (5):455–459. doi: 10.4161/gmic.21216 CrossRefGoogle ScholarPubMed
Serino, M, Luche, E, Gres, S, Baylac, A, Bergé, M, Cenac, C, Waget, A, Klopp, P, Iacovoni, J, Klopp, C, Mariette, J, Bouchez, O, Lluch, J, Ouarné, F, Monsan, P, Valet, P, Roques, C, Amar, J, Bouloumié, A, Théodorou, V, Burcelin, R (2012) Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 61 (4):543–553. doi: 10.1136/gutjnl-2011-301012 CrossRefGoogle ScholarPubMed
Turnbaugh, PJ (2012) Fat, bile and gut microbes. Nature 487 (7405):47–48. doi: 10.1038/487047a CrossRefGoogle ScholarPubMed
Rastelli, M, Knauf, C, Cani, PD (2018) Gut microbes and health: a focus on the mechanisms linking microbes, obesity, and related disorders. Obesity 26 (5):792–800. doi: 10.1002/oby.22175 CrossRefGoogle ScholarPubMed
Cuevas-Sierra, A, Ramos-Lopez, O, Riezu-Boj, JI, Milagro, FI, Martinez, JA (2019) Diet, gut microbiota, and obesity: links with host genetics and epigenetics and potential applications. Adv Nutr 10 (suppl_1):S17–S30. doi: 10.1093/advances/nmy078 CrossRefGoogle ScholarPubMed
Koistinen, VM, Kärkkäinen, O, Borewicz, K, Zarei, I, Jokkala, J, Micard, V, Rosa-Sibakov, N, Auriola, S, Aura, A-M, Smidt, H, Hanhineva, K (2019) Contribution of gut microbiota to metabolism of dietary glycine betaine in mice and in vitro colonic fermentation. Microbiome 7 (1):103. doi: 10.1186/s40168-019-0718-2 CrossRefGoogle ScholarPubMed
Chen, Q, Wang, Y, Jiao, F, Shi, C, Pei, M, Wang, L, Gong, Z (2020) Betaine inhibits Toll-like receptor 4 responses and restores intestinal microbiota in acute liver failure mice. Sci Rep 10 (1):21850. doi: 10.1038/s41598-020-78935-6 CrossRefGoogle ScholarPubMed
Ueland, P, Holm, P, Hustad, S (2005) Betaine: a key modulator of one-carbon metabolism and homocysteine status. Clin Chem Lab Med : CCLM/FESCC 43:1069–1075. doi: 10.1515/CCLM.2005.187 CrossRefGoogle ScholarPubMed
Ommati, MM, Farshad, O, Mousavi, K, Jamshidzadeh, A, Azmoon, M, Heidari, S, Azarpira, N, Niknahad, H, Heidari, R (2020) Betaine supplementation mitigates intestinal barrier disintegrity and bacterial endotoxin translocation in cirrhotic rats. PharmaNutrition:100179. doi: 10.1016/j.phanu.2020.100179 CrossRefGoogle Scholar
Zhu, C, Sawrey-Kubicek, L, Bardagjy, AS, Houts, H, Tang, X, Sacchi, R, Randolph, JM, Steinberg, FM, Zivkovic, AM (2020) Whole egg consumption increases plasma choline and betaine without affecting TMAO levels or gut microbiome in overweight postmenopausal women. Nutr Res 78:36–41. doi: 10.1016/j.nutres.2020.04.002 CrossRefGoogle ScholarPubMed
Aron-Wisnewsky, J, Gaborit, B, Dutour, A, Clement, K (2013) Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect 19 (4):338–348. doi: 10.1111/1469-0691.12140 CrossRefGoogle ScholarPubMed
Machado, MV, Cortez-Pinto, H (2012) Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol 11 (4):440–449 CrossRefGoogle ScholarPubMed
Alipourfard, I, Datukishvili, N, Mikeladze, D (2019) TNF-α downregulation modifies Insulin Receptor Substrate 1 (IRS-1) in metabolic signaling of diabetic insulin-resistant hepatocytes. Mediators Inflamm 2019. https://doi.org/10.1155/2019/3560819 CrossRefGoogle Scholar
Stienstra, R, Saudale, F, Duval, C, Keshtkar, S, Groener, JEM, van Rooijen, N, Staels, B, Kersten, S, Müller, M (2010) Kupffer cells promote hepatic steatosis via interleukin-1β–dependent suppression of peroxisome proliferator-activated receptor α activity. Hepatology 51 (2):511–522. doi: 10.1002/hep.23337 CrossRefGoogle ScholarPubMed
Abu-Shanab, A, Quigley, EMM (2010) The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 7 (12):691–701. doi: 10.1038/nrgastro.2010.172 CrossRefGoogle ScholarPubMed
Alisi, A, Ceccarelli, S, Panera, N, Nobili, V (2012) Causative role of gut microbiota in non-alcoholic fatty liver disease pathogenesis. Front Cell Infect Microbiol 2 (132). doi: 10.3389/fcimb.2012.00132 CrossRefGoogle ScholarPubMed
Zhang, W, Wang, L-w, Wang, L-k, Li, X, Zhang, H, Luo, L-P, Song, J-C, Gong, Z-j (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 (11):3198–3206. doi: 10.1007/s10620-013-2775-x CrossRefGoogle ScholarPubMed
Chen, Y-m, Liu, Y, Zhou, R-f, Chen, X-l, Wang, C, Tan, X-y, Wang, L-j, Zheng, R-d, Zhang, H-w, Ling, W-h, Zhu, H-l (2016) Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep 6:19076–19076. doi: 10.1038/srep19076 CrossRefGoogle ScholarPubMed
Sun, H, Jiang, W-D, Wu, P, Liu, Y, Jiang, J, Yang, Q-H, Kuang, S-Y, Tang, L, Zhou, X-Q, Feng, L (2020) Betaine supplementations enhance the intestinal immunity of on-growing grass carp (Ctenopharyngodon idella): partly related to TOR and NF-κB signaling pathways. Aquaculture 518:734846. doi:10.1016/j.aquaculture.2019.734846 CrossRefGoogle Scholar