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Review

Non-alcoholic fatty liver disease: molecular and cellular interplays of the lipid metabolism in a steatotic liver

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 25-40 | Received 04 May 2020, Accepted 03 Sep 2020, Published online: 14 Sep 2020

References

  • Knell AJ. Liver function and failure: the evolution of liver physiology. J R Coll Physicians Lond. 1980;14(3):205–208.
  • Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4(1):177–197.
  • Tarasenko TN, McGuire PJ. The liver is a metabolic and immunologic organ: A reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM). Mol Genet Metab. 2017;121(4):283–288.
  • Gordillo M, Evans T, Gouon-Evans V. Orchestrating liver development. Development. 2015;142(12):2094–2108.
  • Koo SH. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol. 2013;19(3):210–215.
  • Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13(3):267–276.
  • Preziosi ME, Monga SP. Update on the mechanisms of liver regeneration. Semin Liver Dis. 2017;37(2):141–151.
  • Aguilera-Méndez A, Álvarez-Delgado C, Hernández-Godinez D, et al., Hepatic diseases related to triglyceride metabolism. Mini Rev Med Chem. 2013;13(12): 1691–1699.
  • Forbes S, Vig P, Poulsom R, et al. Hepatic stem cells. J Pathol. 2002;197(4):510–518.
  • Overi D, Carpino G, Cardinale V, et al. Contribution of resident stem cells to liver and biliary tree regeneration in human diseases. Int J Mol Sci. 2018;19(10):2917.
  • The top 10 causes of death. 2018. [cited 2020 May 3]. Available from: http://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death
  • Zhao J, Zhang Z, Luan Y, et al. Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology. 2014;59(4):1331–1342.
  • Bataller R, Gao B. Liver fibrosis in alcoholic liver disease. Semin Liver Dis. 2015;35(2):146–156.
  • Wallace MC, Friedman SL, Mann DA. Emerging and disease-specific mechanisms of hepatic stellate cell activation. Semin Liver Dis. 2015;35(2):107–118.
  • Wallace MC, Friedman SL. Hepatic fibrosis and the microenvironment: fertile soil for hepatocellular carcinoma development. Gene Expr. 2014;16(2):77–84.
  • Raza S, Rajak S, Anjum B, et al. Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma. Hepatoma Res. 2019;5:42.
  • Mantovani A, Scorletti E, Mosca A, et al. Complications, morbidity and mortality of nonalcoholic fatty liver disease. Metabolism. 2020; 154170. DOI:10.1016/j.metabol.2020.154170
  • Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism. 2019;92:82–97.
  • Hui E, Xu A, Bo Yang H, et al. Obesity as the common soil of non-alcoholic fatty liver disease and diabetes: role of adipokines. J Diabetes Investig. 2013;4(5):413–425.
  • Arslan N. Obesity, fatty liver disease and intestinal microbiota. World J Gastroenterol. 2014;20(44):16452–16463.
  • Corey KE, Kaplan LM. Obesity and liver disease: the epidemic of the twenty-first century. Clin Liver Dis. 2014;18(1):1–18.
  • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357.
  • Barros BSV, Santos DC, Pizarro MH, et al. Type 1 diabetes and non-alcoholic fatty liver disease: when should we be concerned? A nationwide study in Brazil. Nutrients. 2017;9(8):878.
  • Araújo AR, Rosso N, Bedogni G, et al. Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: what we need in the future. Liver Int. 2018;38(1):47–51.
  • Anania C, Perla FM, Olivero F, et al. Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol. 2018;24(19):2083–2094.
  • Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the united states. Gastroenterology. 2015;148(3):547–555.
  • Marroni CA, Jr AM F, Fernandes SA, et al. Liver transplantation and alcoholic liver disease: history, controversies, and considerations. World J Gastroenterol. 2018;24(26):2785–2805.
  • Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55(7):434–438.
  • Ikura Y. Transitions of histopathologic criteria for diagnosis of nonalcoholic fatty liver disease during the last three decades. World J Hepatol. 2014;6(12):894–900.
  • Ferramosca A, Zara V. Modulation of hepatic steatosis by dietary fatty acids. World J Gastroenterol. 2014;20(7):1746–1755.
  • Enomoto H, Bando Y, Nakamura H, et al. Liver fibrosis markers of nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21(24):7427–7435.
  • Cai J, Zhang XJ, Li H. Progress and challenges in the prevention and control of nonalcoholic fatty liver disease. Med Res Rev. 2019;39(1):328–348.
  • Stevanović J, Beleza J, Coxito P, et al. Physical exercise and liver “fitness”: role of mitochondrial function and epigenetics-related mechanisms in non-alcoholic fatty liver disease. Mol Metabol. 2019;32:1–14.
  • Wobser H, Dorn C, Weiss TS, et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res. 2009;19(8):996–1005.
  • Lakshman R, Shah R, Reyes-Gordillo K, et al. Synergy between NAFLD and AFLD and potential biomarkers. Clin Res Hepatol Gastroenterol. 2015;39(1):S29–34.
  • Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.
  • Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20.
  • Bettermann K, Hohensee T, Haybaeck J. Steatosis and steatohepatitis: complex disorders. Int J Mol Sci. 2014;15(6):9924–9944.
  • Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–1048.
  • Fang Y, Chai Z, Wang D, et al. DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway. Mol Cell Biochem. 2015;399(1–2):269–278.
  • Conjeevaram Selvakumar PK, Kabbany MN, Alkhouri N. Nonalcoholic fatty liver disease in children: not a small matter. Paediatr Drugs. 2018;20(4):315–329.
  • Rosso N, Chavez-Tapia NC, Tiribelli C, et al. Translational approaches: from fatty liver to non-alcoholic steatohepatitis. World J Gastroenterol. 2014;20(27):9038–9049.
  • Pais R, Barritt AS, Calmus Y, et al. NAFLD and liver transplantation: current burden and expected challenges. J Hepatol. 2016;65(6):1245–1257.
  • Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017;23(36):6549–6570.
  • Lãpãdat AM, Jianu IR, Ungureanu BS, et al. Non-invasive imaging techniques in assessing non-alcoholic fatty liver disease: a current status of available methods. J Med Life. 2016;10(1):19–26.
  • Temple JL, Cordero P, Li J, et al. A guide to non-alcoholic fatty liver disease in childhood and adolescence. Oben Int J Mol Sci. 2016;17(6):947.
  • Hyysalo J, Mannisto VT, Zhou Y, et al. A population-based study on the prevalence of NASH using scores validated against liver histology. J Hepatol. 2014;60(4):839–846.
  • Sorrentino P, Tarantino G, Conca P, et al. Silent non-alcoholic fatty liver disease - a clinical-histological study. J Hepatol. 2004;41(5):751–757.
  • Schwimmer JB, Celedon MA, Lavine JE, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5):1585–1592.
  • Neuman M, Cohen L, Nanau Bsc R. Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2014;28(11):607–616.
  • Hernandez Roman J, Siddiqui M. The role of noninvasive biomarkers in diagnosis and risk stratification in nonalcoholic fatty liver disease. Endocrinol Diabetes Metabol. 2020:e00127.
  • Urasaki Y, Zhang C, Cheng J, et al. Quantitative assessment of liver steatosis and affected pathways with molecular imaging and proteomic profiling. Sci Rep. 2018;8:3606.
  • Lovric A, Granér M, Bjornson E, et al. Characterization of diferent fat depots in NAFLD using infammation-associated proteome, lipidome and metabolome. Sci Rep. 2018;8:14200.
  • Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67(4):829–846.
  • Dumitrascu DL, Neuman MG. Non-alcoholic fatty liver disease: an update on diagnosis. Clujul Med. 2018;91(2):147–150.
  • Filippatos TD, Elisaf MS. Combination drug treatment in patients with non-alcoholic fatty liver disease. World J Hepatol. 2010;2(4):139–142.
  • Siebenhofer A, Jeitler K, Horvath K, et al. Long-term effects of weight-reducing drugs in people with hypertension. Cochrane Database Syst Re. 2016;3:CD007654
  • Mead E, Atkinson G, Richter B, et al. Drug interventions for the treatment of obesity in children and adolescents. Cochrane Database Syst Re. 2016;11:CD012436
  • Ferreira GM, Nazar BP, da Silva MR, et al. Misuse of sibutramine and bulimia nervosa: a dangerous combination. Braz J Psychiatry. 2018;40(3):343.
  • Okuyama H, Langsjoen PH, Hamazaki T, et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015;8(2):189–199.
  • Toth PP, Philip S, Hull M, et al. Elevated triglycerides (≥150 mg/dl) and high triglycerides (200–499 mg/dl) are significant predictors of new heart failure diagnosis: A real-world analysis of high-risk statin-treated patients. Vasc Health Risk Manag. 2019;15:533–538.
  • Lutchman G, Modi A, Kleiner DE, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46(2):424–429.
  • Juurlink DN, Gomes T, Lipscombe LL, et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009;339:b2942.
  • Shiffman M, Freilich B, Vuppalanchi R, et al. Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2019;49(1):64–73.
  • Cao Y, Matsubara T, Zhao C, et al. Antisense oligonucleotide and thyroid hormone conjugates for obesity treatment. Sci Rep. 2017;7:9307.
  • Sinha RA, Bruinstroop E, Singh BK, et al. Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists. Thyroid. 2019;29(9):1173–1191.
  • Silverthorn DU, Ober WC, Garrison CW, et al. Human physiology: an integrated approach. San Francisco: Pearson/Benjamin Cummings; 2010.
  • Nelson DL, Cox MM. Lehninger principles of biochemistry. New York: WH Freeman; 2014.
  • Moustafa T, Fickert P, Magnes C, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology. 2012;142(1):140–151.e12.
  • Juárez-Hernández E, Chávez-Tapia NC, Uribe M, et al. Role of bioactive fatty acids in nonalcoholic fatty liver disease. Nutr J. 2016;15(1):72.
  • Canbay A, Bechmann L, Gerken G. Lipid metabolism in the liver. Z Gastroenterol. 2007;45(1):35–41.
  • Mashek DG. Hepatic fatty acid trafficking: multiple forks in the road. Adv Nutr. 2013;4(6):697–710.
  • Nassir F, Rector RS, Hammoud GM, et al. Pathogenesis and prevention of hepatic steatosis. Gastroenterol Hepatol. 2015;11(3):167–175.
  • Perla FM, Prelati M, Lavorato M, et al. The role of lipid and lipoprotein metabolism in non-alcoholic fatty liver disease. Children (Basel). 2017;4(6):46.
  • Jump DB, Tripathy S, Depner CM. Fatty acid-regulated transcription factors in the liver. Ann Rev Nutr. 2013;33:249–269.
  • Beld J, Lee DJ, Burkart MD. Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering. Mol Biosyst. 2015;11(1):38–59.
  • Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci. 2018;75(18):3313–3327.
  • Schwabe RF, Maher JJ. Lipids in liver disease: looking beyond steatosis. Gastroenterology. 2012;142(1):8–11.
  • Softic S, Cohen DE, Kahn CR. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci. 2016;61(5):1282–1293.
  • Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732–749.
  • Ameer F, Scandiuzzi L, Hasnain S, et al. De novo lipogenesis in health and disease. Metabolism. 2014;63(7):895–902.
  • Jump DB. Mammalian fatty acid elongases. Methods Mol Biol. 2009;579:375–389.
  • Park HG, Engel MG, Vogt-Lowell K, et al. The role of fatty acid desaturase (FADS) genes in oleic acid metabolism: FADS1 Δ7 desaturates 11-20:1 to 7,11-20:2. Prostaglandins Leukot Essent Fatty Acids. 2018;128:21–25.
  • Nguyen P, Leray V, Diez M, et al. Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl). 2008;92(3):272–283.
  • Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008;34(6 Pt 2):643–648.
  • Mouzat K, Chudinova A, Polge A, et al. Regulation of brain cholesterol: what role do liver x receptors play in neurodegenerative diseases? Int J Mol Sci. 2019;20(16):3858.
  • Choudhary M, Ismail EN, Yao P-L, et al. LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target. JCI Insight. 2020;5(1):131928.
  • Lai YS, Yang TC, Chang PY, et al. Electronegative LDL is linked to high-fat, high-cholesterol dietinduced nonalcoholic steatohepatitis in hamsters. J Nutr Biochem. 2016;30:44–52.
  • Akheruzzaman M, Hegde V, Shin AC, et al. Reducing endogenous insulin is linked with protection against hepatic steatosis in mice. Nut Diabetes. 2020;10(1):11.
  • Anstee QM, Day CP. The genetics of nonalcoholic fatty liver disease: spotlight on PNPLA3 and TM6SF2. Semin Liver Dis. 2015;35(3):270–290.
  • Anstee QM, Reeves HL, Kotsiliti E, et al. From NASH to HCC: current concepts and future challenges. Nat Clin Pract Gastroenterol Hepatol. 2019;16(7):411–428.
  • Carlsson B, Lindén D, Brolén G, et al. Review article: the emerging role of genetics in precision medicine for patients with non‐alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51(12):1305–1320.
  • Bruschi FV, Tardelli M, Claudel T, et al. PNPLA3 expression and its impact on the liver current perspectives. Hepat Med. 2017;6:55–66.
  • Basantani MK, Sitnick MT, Cai L, et al. PNPLA3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res. 2011;52(2):318–329.
  • Chen W, Chang B, Li L, et al. Patatin-like phospholipase domaincontaining3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology. 2010;52(3):1134–1142.
  • He S, McPhaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285(9):6706–6715.
  • Merino DM, Johnston H, Clarke S, et al. Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults. Mol Genet Metab. 2011;103(2):171–178.
  • Lattka E, Eggers S, Moeller G, et al. A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1. J Lipid Res. 2010;51(1):182–191.
  • Li Y, Liu S, Gao Y, et al. Association of TM6SF2 rs58542926 gene polymorphism with the risk of non-alcoholic fatty liver disease and colorectal adenoma in Chinese Han population. BMC Biochem. 2019;20(1):3.
  • Cai W, Weng D-H, Yan P, et al. Genetic polymorphisms associated with nonalcoholic fatty liver disease in Uyghur population: a case-control study and meta-analysis. Lipids Health Dis. 2019;18(1):14.
  • Wang C, Gong J, Wu H. Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease. Biomed Rep. 2017;7(2):95–104.
  • de Meneses Fujii TM, Norde MM, Fisberg RM, et al. FADS1 and ELOVL2 polymorphisms reveal associations for differences in lipid metabolism in a cross-sectional populationbased survey of Brazilian men and women. Nut Res. 2020;78:42–49.
  • Ghazalpour A, Cespedes I, Bennett BJ, et al. Expanding role of gut microbiota in lipid metabolism. Curr Opin Lipidol. 2016;27(2):141–147.
  • Schloig S, Arumugam M, Sunagawa S, et al. Genomic variation landscape of the human gut microbiome. Nature. 2013;493(7430):45–50.
  • Devillard E, McIntosh FM, Duncan SH, et al. Metabolism of linoleic acid by human gut bacteria: different routes for biosynthesis of conjugated linoleic acid. J Bacteriol. 2007;189(6):2566–2570.
  • Li X, Li C. Analysis of changes in intestinal flora and intravascular inflammation and coronary heart disease in obese patients. Exp Ther Med. 2018;15(5):4538–4542.
  • Li CY, Dempsey JL, Wang D, et al. PBDEs altered gut microbiome and bile acid homeostasis in male C57BL/6 mice. Drug Metab Dispos. 2018;46(8):1226–1240.
  • Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–1685.
  • Suk KT, Kim DJ. Gut microbiota: novel therapeutic target for nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2019;13(3):193–204.
  • Liu Q, Liu S, Chen L, et al. Role an effective therapeutic target of gut microbiota I NAFLD/NASH (Review). Exp Ther Med. 2019;18(3):1935–1944.
  • Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62:1787–1794.
  • Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci. 2004;101(44):15718–15723.
  • Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, et al. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity? Gastroenterology. 2020;158(7):1881–1898.
  • Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci. 2019;76(8):1541–1558.
  • Chiu -C-C, Ching Y-H, Li Y-P, et al. Nonalcoholic fatty liver disease is exacerbated in high-fat diet-fed gnotobiotic mice by colonization with the gut microbiota from patients with nonalcoholic steatohepatitis. Nutrients. 2017;9(11):1220.
  • Perdomo CM, Frühbeck G. Escalada j.impact of nutritional changes on nonalcoholic fatty liver disease. Nutrients. 2019;11(3):677.
  • Berná G, Romero-Gomez M. The role of nutrition in non-alcoholic fatty liver disease: pathophysiology and management. Liver Int. 2020;40(1):102–108.
  • Sánchez-Tapia M, Tovar AR, Torres N. Diet as regulator of gut microbiota and its role in health and disease. Arch Med Res. 2019;50(5):259–268.
  • Wit NJW, Afman LA, Mensink M, et al. Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol. 2012;57(6):1370–1373.
  • Zelber-Sagi S, Salomone F, Mlynarsky L. The Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: evidence and plausible mechanisms. Liver Int. 2017;37(7):936–949.
  • Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on glycaemic control in patients with abnormal glucose metabolism: A systematic review and meta-analysis. Ann Nutr Metab. 2011;58(4):290–296.
  • López-Miranda J, Pérez-Jiménez F, Ros E, et al. Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain). Nutr Metab Cardiovasc Dis. 2010;20(4):284–294.
  • Tsunoda N, Ikemoto S, Takahashi M, et al. High-monounsaturated fat diet-induced obesity and diabetes in C57BL/6J mice. Metabolism. 1998;47(6):724–730.
  • Hadi E, Zahra Y, Hossein F, et al. Differential effects of dietary fatty acids on body composition and adiposity. Curr Nutri Food Sci. 2020;16(2):142–154.
  • Li X, Sun R, Liu R. Natural products in Licorice for the therapy of liver diseases: progress and future opportunities. Pharmacol Res. 2019;144:210–226.
  • Bagetta D, Maruca A, Lupia A, et al. Mediterranean products as promising source of multi-target agents in the treatment of metabolic syndrome. Eur J Med Chem. 2020;15:111903.
  • Rosqvist F, Kullberg J, Ståhlman M, et al. Overeating saturated fat promotes fatty liver and ceramides compared with polyunsaturated fat: A randomized trial. J Clin Endocrinol Metab. 2019;104(12):6207–6219.
  • Aglago EK, Huybrechts I, Murphy N, et al. Consumption of fish and long-chain n-3 polyunsaturated fatty acids is associated with reduced risk of colorectal cancer in a large European cohort. Clin Gastroenterol Hepatol. 2020;18(3):654–666.
  • De Castro GS, Calder PC. Non-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids. Clin Nutr. 2018;37(1):37–55.
  • Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56(8):365–379.
  • Alferink LJ, Kiefte-de Jong JC, Erler NS, et al. Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam study. Gut. 2019;68(6):1088–1098.
  • Tetri LH, Basaranoglu M, Brunt EM, et al. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):987–995.
  • Neuschwander-Tetri BA, Ford DA, Acharya S, et al. Dietary trans-fatty acid induced NASH is normalized following loss of trans-fatty acids from hepatic lipid pools. Lipids. 2012;47(10):941–950.
  • Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol. 2015;31(1):69–75.
  • Hendrikx T, Schnabl B. Antimicrobial proteins: intestinal guards to protect against liver disease. J Gastroenterol. 2019;54(3):209–217.
  • Devkota S, Chang EB. Nutrition, microbiome, and intestinal inflammatrion. Curr Opin Gastroenterol. 2013;29(6):603–607.
  • Sáez-lara MJ, Robles-Sánchez C, Ruiz-ojeda FJ, et al. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: A review of human clinical trials. Int J Mol Sci. 2016;17(6):928.
  • Federico A, Dallio M, Godos J, et al. Targeting gut-liver axis for the treatment of nonalcoholic steatohepatitis: translational and clinical evidence. Transl Res. 2016;167(1):116–124.
  • Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823–1836.
  • Liu X, Green RM. Beyond FXR to target new therapies for NAFLD. Hepatology. 2017;66(6):1724–1726.
  • Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–585.
  • Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17(1):49–60.
  • Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63.
  • Shih DM, Wang Z, Lee R, et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J Lipid Res. 2015;56(1):22–37.
  • Warrier M, Shih DM, Burrows AC, et al. The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 2015;10(3):326–338.
  • Pirola CJ, Gianotti TF, Burgueno AL, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut. 2013;62:1356–1363.
  • Yu H-L, Dong S, Gao L-F, et al. Global DNA methylation was changed by a maternal high-lipid, high-energy diet during gestation and lactation in male adult mice liver. Br J Nutr. 2015;113(7):1032–1039.
  • Mathers JC, McKay JA. Epigenetics - potential contribution to fetal programming. Adv Exp Med Biol. 2009;646:119–123.
  • Burdge GC, Lillycrop KA, Acids F. Epigenetics. Curr Opin Clin Nutr Metab Care. 2014;17(2):156–161.
  • Benatti RO, Mello AM, Borges FO, et al. Maternal high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370) expression in offspring. Br J Nutr. 2014;111(12):2112–2122.
  • Zheng J, Zhang Q, Mul JD. Maternal high-calorie diet is associated with altered hepatic microRNA expression and impaired metabolic health in offspring at weaning age. Endocrine. . 2016;54(1):70–80.
  • Zilberman D, Henikoff S. Genome-wide analysis of DNA methylation patterns. Development. 2007;134(22):3959–3965.
  • Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013;38(1):23–38.
  • Merlo A, Herman JG, Mao L, et al. 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686–692.
  • Choi SW, Epigenetics FS, New A. Bridge between nutrition and health. Adv Nutr. 2010;1(1):8–16.
  • Lee J, Kim Y, Friso S, et al. Epigenetics in non-alcoholic fatty liver disease. Mol Aspects Med. 2017;54:78–88.
  • Mann DA. Epigenetics in liver disease. Hepatology. 2014;60(4):1418–1425.
  • Hardy T, Mann DA. Epigenetics in liver disease: from biology to therapeutics.  Gut. 2016;65(11):1895–1905.
  • Pirola CJ, Fernández Gianotti T, Castaño GO, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut. 2015;64(5):800–812.
  • Lee JH, Friso S, Choi SW. Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients. 2014;6(8):3025–3303.
  • Park LK, Friso S, Choi SW. Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc. 2012;71(1):75–83.
  • da Silva RP, Kelly KB, Al Rajabi A, et al. Novel insights on interactions between folate and lipid metabolism. Biofactors. 2014;40(3):277–283.
  • Wang LJ, Zhang HW, Zhou JY, et al. 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. 2014;25(3):329–336.
  • Sookoian S, Rosselli MS, Gemma C, 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.
  • Murphy SK, Yang H, Moylan CA, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145(5):1076–1087.
  • Tryndyak VP, Han T, Fuscoe JC, et al. Status of hepatic DNA methylome predetermines and modulates the severity of non-alcoholic fatty liver injury in mice. BMC Genomics. 2016;17:298.
  • Gerhard GS, Malenica I, Llaci L, et al. Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways. Clin Epigenetics. 2018;10(1):93.
  • Chen ZJ, Pikaard CS. Epigenetic silencing of RNA polymerase I transcription: a role for DNA methylation and histone modification in nucleolar dominance. Genes Dev. 1997;11(16):2124–2136.
  • Gallego-Durán R, Romero-Gómez M. Epigenetic mechanisms in non-alcoholic fatty liver disease: an emerging field. World J Hepatol. 2015;7(24):2497–2502.
  • Granger A, Abdullah I, Huebner F, et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. Faseb J. 2008;22(10):3549–3560.
  • Chung MY, Song JH, Lee J, et al. Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. Mol Metab. 2019;19:34–48.
  • Tian Y, Wong VW, Chan HL, et al. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin Cancer Biol. 2013;23(6 Pt B):471–482.
  • Cai C, Yu H, Huang G, et al. Histone modifications in fatty acid synthase modulated by carbohydrate responsive element binding protein are associated with nonalcoholic fatty liver disease. Int J Mol Med. 2018;42(3):1215–1228.
  • Du X, Cai C, Yao J, et al. Histone modifications in FASN modulated by sterol regulatory element-binding protein 1c and carbohydrate responsive-element binding protein under insulin stimulation are related to NAFLD. Biochem Biophys Res Commun. 2017;483(1):409–417.
  • Feng D, Liu T, Sun Z, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331(6022):1315–1319.
  • Sun Z, Miller RA, Patel RT, et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med. 2012;18(6):934–942.
  • Colak Y, Ozturk O, Senates E, et al. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med Sci Monit. 2011;17(5):HY5–HY9.
  • Li F, Li H, Jin X, et al. Adipose-specific knockdown of Sirt1 results in obesity and insulin resistance by promoting exosomes release. Cell Cycle. 2019;18(17):2067–2082.
  • Suter MA, Chen A, Burdine MS, et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. Faseb J. 2012;26(12):5106–5114.
  • Cao Y, Xue Y, Xue L, et al. Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation. J Hepatol. 2013;59(6):1299–1306.
  • van Rooij E, Kauppinen S. Development of microRNA therapeutics is coming of age. EMBO Mol Med. 2014;6(7):851–864.
  • Loosen SH, Schueller F, Trautwein C, et al. Role of circulating microRNAs in liver diseases. World J Hepatol. 2017;9(12):586–594.
  • Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–355.
  • Bhaskaran M, Mohan M. MicroRNAs: history, biogenesis, and their evolving role in animal development and disease. Vet Pathol. 2014;51(4):759–774.
  • Awasthi R, Rathbone MJ, Hansbro PM, et al. Therapeutic prospects of microRNAs in cancer treatment through nanotechnology. Drug Deliv Transl Res. 2018;8(1):97–110.
  • Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15(8):509–524.
  • Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Rev Drug Discov. 2014;13(8):622–638.
  • Erson-Bensan AE. Introduction to microRNAs in biological systems. Methods Mol Biol. 2014;1107:1–14.
  • Berezikov E, Chung WJ, Willis J, et al. Mammalian mirtron genes. Mol Cell. 2007 Oct 26;28(2):328–336.
  • Okamura K, Hagen JW, Duan H, et al. The mirtron pathway generates microRNA-class regulatory RNAs in drosophila. Cell. 2007;130(1):89–100.
  • Ruby JG, Jan CH, Bartel DP. Intronic microRNA precursors that bypass Drosha processing. Nature. 2007;448(7149):83–86.
  • Simonson B, Das S. MicroRNA therapeutics: the next magic bullet? Mini Rev Med Chem. 2015;15(6):467–474.
  • Jiang X, Tsitsiou E, Herrick SE, et al. MicroRNAs and the regulation of fibrosis. Febs J. 2010;277(9):2015–2021.
  • Guo CJ, Pan Q, Li DG, et al. miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: an essential role for apoptosis. J Hepatol. 2009;50(4):766–778.
  • Guo CJ, Pan Q, Xiong H, et al. Therapeutic potential of microRNA: a new target to treat intrahepatic portal hypertension? Biomed Res Int. 2014;2014:797898.
  • Akbari Moqadam F, Pieters R, den Boer ML. The hunting of targets: challenge in miRNA research. Leukemia. 2013;27(1):16–23.
  • Laganà A. Computational prediction of microRNA targets. Adv Exp Med Biol. 2015;887:231–252.
  • Dongiovanni P, Meroni M, Longo M, et al. miRNA signature in NAFLD: A turning point for a non-invasive diagnosis. Int J Mol Sci. 2018;19(12):pii: E3966.
  • Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 2013;10(9):542–552.
  • Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–222.
  • Schmidt MF. Drug target miRNAs: chances and challenges. Trends Biotechnol. 2014;32(11):578–585.
  • Wang Y, Chen T, Tong W. miRNAs and their application in drug-induced liver injury. Biomark Med. 2014;8(2):161–172.
  • Schwarzenbach H. The clinical relevance of circulating, exosomal miRNAs as biomarkers for cancer. Expert Rev Mol Diagn. 2015;15(9):1159–1169.
  • Sobolewski C, Calo N, Portius D, et al. MicroRNAs in fatty liver disease. Semin Liver Dis. 2015;35(1):12–25.
  • Huan L, Liang LH, He XH. Role of microRNAs in inflammation-associated liver cancer. Cancer Biol Med. 2016 Dec;13(4):407–425.
  • Del Campo JA, Gallego-Durán R, Gallego P, et al., Genetic and epigenetic regulation in nonalcoholic fatty liver disease (NAFLD). Int J Mol Sci. 2018;19(3): pii: E911.
  • Takaki Y, Saito Y, Takasugi A, et al. Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis. Cancer Sci. 2014;105(10):1254–1260.
  • Li ZY, Xi Y, Zhu WN, et al. Positive regulation of hepatic miR-122 expression by HNF4a. J Hepatol. 2011;55(3):602–611.
  • Yamada H, Suzuki K, Ichino N, et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta. 2013;424:99–103.
  • Cermelli S, Ruggieri A, Marrero JA, et al. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011;6(8):e23937.
  • Zheng L, Lv GC, Sheng J, et al. Effect of miRNA-10b in regulating cellular steatosis level by targeting PPAR-α expression, a novel mechanism for the pathogenesis of NAFLD. J Gastroenterol Hepatol. 2010;25(1):156–163.
  • Sun C, Fan J-G QL. Potential epigenetic mechanism in non-alcoholic fatty liver disease. Int J Mol Sci. 2015;16(3):5161–5179.
  • Tryndyak VP, Latendresse JR, Montgomery B, et al. Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet. Toxicol Appl Pharmacol. 2012;262(1):52–59.
  • Quinn J, Chang H. Unique features of long non-coding RNA biogenesis and function. Nat Rev. 2016;17(1):47–62.
  • Marchese F, Raimondi I, Huarte M. The multidimensional mechanisms of long noncoding RNA function. Genome Biol. 2017;18(1):206.
  • Dhanoa J, Sethi R, Verma R, et al. Long non-coding RNA: its evolutionary relics and biological implications in mammals: a review. J Animal Sci Technol. 2018;60:25.
  • Mishra K, Kanduri C. Understanding long noncoding RNA and chromatin interactions: what we know so far. Noncoding RNA. 2019;5(4):54.
  • Sun C, Liu X, Yi Z, et al. Genome-wide analysis of long noncoding RNA expression profiles in patients with non-alcoholic fatty liver disease. Int Univ Biochem Mol Biol. 2015;67(11):847–852.
  • Chen Y, Huang H, Xu C, et al. Long non-coding RNA profiling in a non-alcoholic fatty liver disease rodent model: new insight into pathogenesis. Int J Mol Sci. 2017;18(1):21.
  • Chen X, Xu Y, Zhao D, et al. LncRNA-AK012226 Is involved in fat accumulation in db/db mice fatty liver and non-alcoholic fatty liver disease cell model. Front Pharmacol. 2018;9:888.
  • Shen X, Guo H, Xu J, et al. Inhibition of lncRNA HULC improves hepatic fibrosis and hepatocyte apoptosis by inhibiting the MAPK signaling pathway in rats with nonalcoholic fatty liver disease. J Cell Physiol. 2019;234(10):18169-18179.
  • Wang X. Down-regulation of lncRNA-NEAT1 alleviated the non-alcoholic fatty liver disease via mTOR/S6K1 signaling pathway. J Cell Biochem. 2018;119(2):1567–1574.
  • Wang H, Cao Y, Shu L, et al. Long non-coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes. J Cell Mol Med. 2020;24(2):1399–1412.
  • Zhang Q, Wang J, Li H, et al. LncRNA Gm12664–001 ameliorates nonalcoholic fatty liver through modulating miR-295-5p and CAV1 expression. Nutri Metabol. 2020;17:13.
  • Liu F, Chen Q, Chen F, et al. The lncRNA ENST00000608794 acts as a competing endogenous RNA to regulate PDK4 expression by sponging miR-15b-5p in dexamethasone induced steatosis. BBA – Mol Cell Bio of Lipids. 2019;1864(10):1449–1457.
  • Sun Y, Song Y, Liu C, et al. LncRNA NEAT1-microRNA-140 axis exacerbates nonalcoholic fatty liver through interrupting AMPK/SREBP-1 signaling. Biochem Biophys Res Commun. 2019;516(2):584–590.
  • Zhang LH, Li D, Li D, et al. Long noncoding RNA mirt2 upregulates USP10 expression to suppress hepatic steatosis by sponging miR-34a-5p. Gene. 2019;700:139–148.

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