Review on the Role of Fructose in Non-Alcoholic Fatty Liver Diseases

Isaac John Umaru1 and Okoli Chikodiri Emmanuel2
1Department of Biochemistry, Federal University Wukari, Taraba State. Nigeria
2Department de Chimie Inorganique Faculté des Sciences Universite de Yaoundé 1. Cameroon
DOI – http://doi.org/10.37502/IJSMR.2022.5212

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a clinical liver condition characterized by accumulation of fat in the liver that can develop into non-alcoholic steatohepatitis (NASH) without any evidence of excessive alcohol consumption. NASH involves liver inflammation, necrosis, fibrosis, cirrhosis, and eventually liver cancer. Excessive intake of fructose is known to promote non-alcoholic fatty liver (NAFLD), because this sugar is both a substrate and an inducer of liver fat regeneration. In addition to the hepatic lipogenic effects, the consumption of fructose can also cause liver inflammation and cellular stress, such as oxidative and endoplasmic stress, which are conducive to the progression of steatosis to non-alcoholic steatohepatitis (NASH). Fructose also has direct and indirect effects on peripheral levels. For example, excessive fructose intake is associated with changes in the gut microbiota, which can lead to a worsening of the disease. Currently, there is no known treatment for NAFLD. Therefore, treatment is based on lifestyle changes, including changes in diet and physical exercise.

Keywords: Role, Fructose, Non-Alcoholic, Fatty, Liver, Diseases

References

  • Harrison, S. A., Goodman, Z., Jabbar, A., Vemulapalli, R., Younes, Z. H., Freilich, B., Sheikh, M. Y., Schattenberg, J. M., Kayali, Z., Zivony, A., Sheikh, A., Garcia-Samaniego, J., Satapathy, S. K., Therapondos, G., Mena, E., Schuppan, D., Robinson, J., Chan, J. L., Hagerty, D. T., & Sanyal, A. J. (2020). A randomized, placebo-controlled trial ofemricasan in patients with NASH and F1-F3 fibrosis. Journal of hepatology, 72(5), 816–827. https://doi.org/10.1016/j.jhep.2019.11.024
  • Alexander, M., Loomis, A. K., van der Lei, J., Duarte-Salles, T., Prieto-Alhambra, D., Ansell, D., Pasqua, A., Lapi, F., Rijnbeek, P., Mosseveld, M., Waterworth, D. M., Kendrick, S., Sattar, N., & Alazawi, W. (2019). Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC medicine, 17(1), 95. https://doi.org/10.1186/s12916-019-1321-x
  • Krenkel, O., Puengel, T., Govaere, O., Abdallah, A. T., Mossanen, J. C., Kohlhepp, M., Liepelt, A., Lefebvre, E., Luedde, T., Hellerbrand, C., Weiskirchen, R., Longerich, T., Costa, I. G., Anstee, Q. M., Trautwein, C., & Tacke, F. (2018). Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology (Baltimore, Md.), 67(4), 1270–1283. https://doi.org/10.1002/hep.29544.
  • Lefere, S., Devisscher, L., & Tacke, F. (2020). Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges. Expert opinion on investigational drugs, 29(2), 89–92. https://doi.org/10.1080/13543784.2020.1718106
  • Ratziu, V., Harrison, S. A., Francque, S., Bedossa, P., Lehert, P., Serfaty, L., Romero-Gomez, M., Boursier, J., Abdelmalek, M., Caldwell, S., Drenth, J., Anstee, Q. M., Hum, D., Hanf, R., Roudot, A., Megnien, S., Staels, B., Sanyal, A., & GOLDEN-505 Investigator Study Group (2016). Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces esolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology, 150(5), 1147–1159.e5 https://doi.org/10.1053/j.gastro.2016.01.038
  • Staels, B., Rubenstrunk, A., Noel, B., Rigou, G., Delataille, P., Millatt, L. J., Baron, M., Lucas, A., Tailleux, A., Hum, D. W., Ratziu, V., Cariou, B., & Hanf, R. (2013). Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology (Baltimore, Md.), 58(6), 1941–1952. https://doi.org/10.1002/hep.26461
  • Delerive, P., De Bosscher, K., Besnard, S., Vanden Berghe, W., Peters, J. M., Gonzalez, F. J., Fruchart, J. C., Tedgui, A., Haegeman, G., & Staels, B. (1999). Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappa B and AP-1. The Journal of biological chemistry, 274(45), 32048–32054. https://doi.org/10.1074/jbc.274.45.32048
  • Tsuchida, T., Lee, Y. A., Fujiwara, N., Ybanez, M., Allen, B., Martins, S., Fiel, M. I., Goossens, N., Chou, H. I., Hoshida, Y., & Friedman, S. L. (2018). A simple diet and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. Journal of hepatology, 69(2), 385–395. https://doi.org/10.1016/j.jhep.2018.03.011
  • Shiri-Sverdlov, R., Wouters, K., van Gorp, P. J., Gijbels, M. J., Noel, B., Buffat, L., Staels, B., Maeda, N., van Bilsen, M., & Hofker, M. H. (2006). Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. Journal of hepatology, 44(4), 732–741. https://doi.org/10.1016/j.jhep.2005.10.033
  • Pearson, S., Kietsiriroje, N., & Ajjan, R. A. (2019). Oral Semaglutide ; In The Management of Type 2 Diabetes: A Report On The Evidence To Date. Diabetes, metabolic syndrome and obesity: targets and therapy, 12, 2515–2529. https://doi.org/10.2147/DMSO.S229802
  • Newsome, P., Francque, S., Harrison, S., Ratziu, V., Van Gaal, L., Calanna, S., Hansen, M., Linder, M., & Sanyal, A. (2019). Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Alimentary pharmacology & therapeutics, 50(2), 193–203. https://doi.org/10.1111/apt.15316
  • Sun, X., Duan, X., Wang, C., Liu, Z., Sun, P., Huo, X., Ma, X., Sun, H., Liu, K., & Meng, Q. (2017). Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice. European journal of pharmacology, 806, 75–82. https://doi.org/10.1016/j.ejphar.2017.04.021
  • Challa, T. D., Wueest, S., Lucchini, F. C., Dedual, M., Modica, S., Borsigova, M., Wolfrum, C., Blüher, M., & Konrad, D. (2019). Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis. EMBO molecular medicine, 11(10), e10124. https://doi.org/10.15252/emmm.201810124
  • Federico, A., Rosato, V., Masarone, M., Torre, P., Dallio, M., Romeo, M., & Persico, M. (2021). The Role of Fructose in Non-Alcoholic Steatohepatitis: Old Relationship and New Insights. Nutrients, 13(4), 1314. https://doi.org/10.3390/nu13041314
  • Kumar, R., & Mohan, S. (2017). Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications. Journal of clinical and translational hepatology, 5(3), 216–223. https://doi.org/10.14218/JCTH.2016.00068
  • Simons, N., Debray, F. G., Schaper, N. C., Kooi, M. E., Feskens, E., Hollak, C., Lindeboom, L., Koek, G. H., Bons, J., Lefeber, D. J., Hodson, L., Schalkwijk, C. G., Stehouwer, C., Cassiman, D., & Brouwers, M. (2019). Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content. The Journal of clinical endocrinology and metabolism, 104(11), 5056–5064. https://doi.org/10.1210/jc.2018-02795
  • Cardoso, A. C., de Figueiredo-Mendes, C., & A Villela-Nogueira, C. (2021). Current management of NAFLD/NASH. Liver international: official journal of the International Association for the Study of the Liver, 41 Suppl 1, 89–94. https://doi.org/10.1111/liv.14869
  • Ratziu, V., Goodman, Z., & Sanyal, A. (2015). Current efforts and trends in the treatment of NASH. Journal of Hepatology, 62(1 Suppl), S65–S75. https://doi.org/10.1016/j.jhep.2015.02.041
  • Munteanu, M. A., Nagy, G. A., & Mircea, P. A. (2016). Current Management of NAFLD. Clujul medical (1957), 89(1), 19–23. https://doi.org/10.15386/cjmed-539
  • Pradeepa, R., Anjana, R. M., Joshi, S. R., Bhansali, A., Deepa, M., Joshi, P. P., Dhandania, V. K., Madhu, S. V., Rao, P. V., Geetha, L., Subashini, R., Unnikrishnan, R., Shukla, D. K., Kaur, T., Mohan, V., Das, A. K., & ICMR-INDIAB Collaborative Study Group (2015). Prevalence of generalized & abdominal obesity in urban & rural India–the ICMR-INDIAB Study (Phase-I) [ICMR- NDIAB-3]. The Indian Journal of Medical Research, 142(2), 139–150. https://doi.org/10.4103/0971-5916.164234
  • Marjot, T., Moolla, A., Cobbold, J. F., Hodson, L., & Tomlinson, J. W. (2020). Nonalcoholic Fatty Liver Disease in Adults: Current Concepts in Etiology, Outcomes, and Management. Endocrine reviews, 41(1), bnz009. https://doi.org/10.1210/endrev/bnz009
  • Majumdar, A., Misra, P., Sharma, S., Kant, S., Krishnan, A., & Pandav, C. S. (2016). Prevalence of nonalcoholic fatty liver disease in an adult population in a rural community of Haryana, India. Indian journal of public health, 60(1), 26–33. https://doi.org/10.4103/0019-557X.177295
  • Dai, W., Ye, L., Liu, A., Wen, S. W., Deng, J., Wu, X., & Lai, Z. (2017). Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: A meta-analysis. Medicine, 96(39), e8179. https://doi.org/10.1097/MD.0000000000008179
  • Younossi, Z., Anstee, Q. M., 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. Nature reviews. Gastroenterology & hepatology, 15(1), 11–20. https://doi.org/10.1038/nrgastro.2017.109
  • Kalafati, I. P., Borsa, D., Dimitriou, M., Revenas, K., Kokkinos, A., & Dedoussis, G. V. (2019). Dietary patterns and non-alcoholic fatty liver disease in a Greek case-control study. Nutrition (Burbank, Los Angeles County, Calif.), 61, 105–110. https://doi.org/10.1016/j.nut.2018.10.032
  • Wehmeyer, M. H., Zyriax, B. C., Jagemann, B., Roth, E., Windler, E., Schulze Zur Wiesch, J., Lohse, A. W., & Kluwe, J. (2016). Nonalcoholic fatty liver disease is associated with excessive calorie intake rather than a distinctive dietary pattern. Medicine, 95(23), e3887. https://doi.org/10.1097/MD.0000000000003887
  • Aller, R., Izaola, O., de la Fuente, B., & De Luis Román, D. A. (2015). Mediterranean diet is associated with liver histology in patients with nonalcoholic fatty liver disease.Nutricion hospitalaria, 32(6), 2518–2524. https://doi.org/10.3305/nh.2015.32.6.10074
  • Cheng, S., Ge, J., Zhao, C., Le, S., Yang, Y., Ke, D., Wu, N., Tan, X., Zhang, X., Du, X., Sun, J., Wang, R., Shi, Y., Borra, R., Parkkola, R., Wiklund, P., & Lu, D. (2017). Effect of aerobic exercise and diet on liver fat in pre-diabetic patients with non-alcoholic-fatty-liver-disease: A randomized controlled trial. Scientific reports, 7(1), 15952. https://doi.org/10.1038/s41598-017-16159-x
  • Armstrong, M. J., Gaunt, P., Aithal, G. P., Barton, D., Hull, D., Parker, R., Hazlehurst, J. M., Guo, K., LEAN trial team, Abouda, G., Aldersley, M. A., Stocken, D., Gough, S. C., Tomlinson, J. W., Brown, R. M., Hübscher, S. G., & Newsome, P. N. (2016). Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet (London, England), 387(10019), 679–690. https://doi.org/10.1016/S0140-6736(15)00803-X
  • Della Corte, C., Mosca, A., Vania, A., Alterio, A., Iasevoli, S., & Nobili, V. (2017). Good adherence to the Mediterranean diet reduces the risk for NASH and diabetes in pediatric patients with obesity: The results of an Italian Study. Nutrition (Burbank, Los Angeles County, Calif.), 39-40, 8–14. https://doi.org/10.1016/j.nut.2017.02.008
  • Anania, C., Perla, F. M., Olivero, F., Pacifico, L., & Chiesa, C. (2018). Mediterranean diet and nonalcoholic fatty liver disease. World journal of gastroenterology, 24(19), 2083–2094.https://doi.org/10.3748/wjg.v24.i19.2083
  • Maersk, M., Belza, A., Stødkilde-Jørgensen, H., Ringgaard, S., Chabanova, E., Thomsen, H., Pedersen, S. B., Astrup, A., & Richelsen, B. (2012). Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. The American journal of clinical nutrition, 95(2), 283–289. https://doi.org/10.3945/ajcn.111.022533
  • Jensen, T., Abdelmalek, M. F., Sullivan, S., Nadeau, K. J., Green, M., Roncal, C., Nakagawa, T., Kuwabara, M., Sato, Y., Kang, D. H., Tolan, D. R., Sanchez-Lozada, L. G., Rosen, H. R., Lanaspa, M. A., Diehl, A. M., & Johnson, R. J. (2018). Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. Journal of hepatology, 68(5), 1063–1075. https://doi.org/10.1016/j.jhep.2018.01.019
  • Choi, Y. J., Shin, H. S., Choi, H. S., Park, J. W., Jo, I., Oh, E. S., Lee, K. Y., Lee, B. H., Johnson, R. J., & Kang, D. H. (2014). Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Laboratory Investigation; a journal of technical methods and pathology, 94(10), 1114–1125. https://doi.org/10.1038/labinvest.2014.98
  • Armandi, A., & Bugianesi, E. (2021). Natural history of NASH. Liver international: official Journal of the International Association for the Study of the Liver, 41 Suppl 1, 78–82. https://doi.org/10.1111/liv.14910
  • Bian, E. B., Zhao, B., Huang, C., Wang, H., Meng, X. M., Wu, B. M., Ma, T. T., Zhang, L., Lv, W., & Li, J. (2013). New advances of DNA methylation in liver fibrosis, with special emphasis on the crosstalk between microRNAs and DNA methylation machinery. Cellular signalling, 25(9), 1837–1844. https://doi.org/10.1016/j.cellsig.2013.05.017
  • Lee, J. H., Friso, S., & Choi, S. W. (2014). Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients, 6(8), 3303–3325. https://doi.org/10.3390/nu6083303
  • Bril, F., Portillo-Sanchez, P., Liu, I. C., Kalavalapalli, S., Dayton, K., & Cusi, K. (2018). Clinical and Histologic Characterization of Nonalcoholic Steatohepatitis in African American Patients. Diabetes care, 41(1), 187–192. https://doi.org/10.2337/dc17-1349
  • Menke, A., Casagrande, S., Geiss, L., & Cowie, C. C. (2015). Prevalence of and Trends in Diabetes among Adults in the United States, 1988-2012. JAMA, 314(10), 1021–1029. https://doi.org/10.1001/jama.2015.10029
  • Li, J., Zou, B., Yeo, Y. H., Feng, Y., Xie, X., Lee, D. H., Fujii, H., Wu, Y., Kam, L. Y., Ji, F., Li, X., Chien, N., Wei, M., Ogawa, E., Zhao, C., Wu, X., Stave, C. D., Henry, L., Barnett, S., Takahashi, H., Nguyen, M. H. (2019). Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. The lancet. Gastroenterology & hepatology, 4(5), 389–398. https://doi.org/10.1016/S2468-1253(19)30039-1
  • Fan, J. G., Kim, S. U., & Wong, V. W. (2017). New trends on obesity and NAFLD in Asia. Journal of hepatology, 67(4), 862–873. https://doi.org/10.1016/j.jhep.2017.06.003
  • Misra, A., Soares, M. J., Mohan, V., Anoop, S., Abhishek, V., Vaidya, R., & Pradeepa, R. (2018). Body fat, metabolic syndrome and hyperglycemia in South Asians. Journal of diabetes and its complications, 32(11), 1068–1075. https://doi.org/10.1016/j.jdiacomp.2018.08.001
  • Ballestri, S., Nascimbeni, F., Baldelli, E., Marrazzo, A., Romagnoli, D., & Lonardo, A. (2017).NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk. Advances in therapy, 34(6), 1291–1326. https://doi.org/10.1007/s12325-017-0556-1
  • Florentino, G. S., Cotrim, H. P., Vilar, C. P., Florentino, A. V., Guimarães, G. M., & Barreto, V. S. (2013). Nonalcoholic fatty liver disease in menopausal women. Arquivos de gastroenterologia, 50(3), 180–185. https://doi.org/10.1590/S0004-28032013000200032
  • Argo, C. K., Northup, P. G., Al-Osaimi, A. M., & Caldwell, S. H. (2009). Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. Journal of hepatology, 51(2), 371–379. https://doi.org/10.1016/j.jhep.2009.03.019
  • Klair, J. S., Yang, J. D., Abdelmalek, M. F., Guy, C. D., Gill, R. M., Yates, K., Unalp-Arida, A., Lavine, J. E., Clark, J. M., Diehl, A. M., Suzuki, A., & Nonalcoholic Steatohepatitis Clinical Research Network (2016). A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.), 64(1), 85–91. https://doi.org/10.1002/hep.28514
  • Wang, S., Sun, H., Xie, Z., Li, J., Hong, G., Li, D., Mallampati, S., Zhou, X., Zhou, C., Zhang, H., Cheng, Z., Shan, H., & Ma, H. (2016). Improved survival of patients with hepatocellular carcinoma and disparities by age, race, and socioeconomic status by decade, 1983-2012.Oncotarget, 7(37), 59820–59833. https://doi.org/10.18632/oncotarget.10930
  • Carr, R. M., Oranu, A., & Khungar, V. (2016). Nonalcoholic Fatty Liver Disease: Pathophysiology and Management. Gastroenterology clinics of North America, 45(4), 639–652. https://doi.org/10.1016/j.gtc.2016.07.003
  • Angulo, P., Kleiner, D.E., Dam-Larsen, S., Adams, L.A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P.R., Keach, J.C., Lafferty, H. D., Stahler, A., Haflidadottir, S., & Bendtsen, F. (2015). Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology, 149(2), 389–97.e10. https://doi.org/10.1053/j.gastro.2015.04.043
  • Bhattacharjee, J., Kumar, J. M., Arindkar, S., Das, B., Pramod, U., Juyal, R. C., Majumdar, S. S., & Nagarajan, P. (2014). Role of immunodeficient animal models in the development of fructose induced NAFLD. The Journal of nutritional biochemistry, 25(2), 219–226. https://doi.org/10.1016/j.jnutbio.2013.10.010
  • Lisboa, Q. C., Costa, S. M., & Couto, C. A. (2016). Current management of non-alcoholic fatty liver disease. Revista da Associacao Medica Brasileira (1992), 62(9), 872–878. https://doi.org/10.1590/1806-9282.62.09.872
  • Kupčová, V., Fedelešová, M., Bulas, J., Kozmonová, P., & Turecký, L. (2019). Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD. International journal of environmental research and public health, 16(19), 3570. https://doi.org/10.3390/ijerph16193570
  • HaGani, N., Moran, M. R., Caspi, O., Plaut, P., Endevelt, R., & Baron-Epel, O. (2019). The Relationships between Adolescents’ Obesity and the Built Environment: Are They City Dependent? International journal of environmental research and public health, 16(9), 1579. https://doi.org/10.3390/ijerph16091579
  • Bessone, F., Razori, M. V., & Roma, M. G. (2019). Molecular pathways of nonalcoholic fatty liver disease development and progression. Cellular and Molecular Life Sciences: CMLS, 76(1), 99–128. https://doi.org/10.1007/s00018-018-2947-0
  • Pierantonelli, I., & Svegliati-Baroni, G. (2019). Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH. Transplantation, 103(1), e1–e13. https://doi.org/10.1097/TP.0000000000002480
  • Ajmera, V., Perito, E. R., Bass, N. M., Terrault, N. A., Yates, K. P., Gill, R., Loomba, R., Diehl, A. M., Aouizerat, B. E., & NASH Clinical Research Network (2017). Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.), 65(1), 65–77. https://doi.org/10.1002/hep.28776
  • Alexander, M., Loomis, A. K., van der Lei, J., Duarte-Salles, T., Prieto-Alhambra, D., Ansell, D., Pasqua, A., Lapi, F., Rijnbeek, P., Mosseveld, M., Waterworth, D. M., Kendrick, S., Sattar, N., & Alazawi, W. (2019). Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC medicine, 17(1), 95. https://doi.org/10.1186/s12916-019-1321-x
  • Alwahsh, S. M., Xu, M., Seyhan, H. A., Ahmad, S., Mihm, S., Ramadori, G., & Schultze, F. C. (2014). Diet high in fructose leads to an overexpression of lipocalin-2 in rat fatty liver. World journal of gastroenterology, 20(7),          1807–1821. https://doi.org/10.3748/wjg.v20.i7.1807
  • Armstrong, M. J., Gaunt, P., Aithal, G. P., Barton, D., Hull, D., Parker, R., Hazlehurst, J. M., Guo, K., LEAN trial team, Abouda, G., Aldersley, M. A., Stocken, D., Gough, S. C., Tomlinson, J. W., Brown, R. M., Hübscher, S. G., & Newsome, P. N. (2016). Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet (London, England), 387(10019), 679–690. https://doi.org/10.1016/S0140-6736(15)00803-X
  • Armstrong, M. J., Hull, D., Guo, K., Barton, D., Hazlehurst, J. M., Gathercole, L. L., Nasiri, M., Yu, J., Gough, S. C., Newsome, P. N., & Tomlinson, J. W. (2016). Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. Journal of Hepatology, 64(2), 399–408. https://doi.org/10.1016/j.jhep.2015.08.038
  • Banini, B. A., & a, A. J. (2016). Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural History, Diagnosis, and Current Treatment Options. Clinical medicine insights. Therapeutics, 8, 75–84. https://doi.org/10.4137/cmt.s18885
  • Bhattacharjee, J., Kumar, J. M., Arindkar, S., Das, B., Pramod, U., Juyal, R. C., Majumdar, S. S., & Nagarajan, P. (2014). Role of immunodeficient animal models in the development of fructose induced NAFLD. The Journal of nutritional biochemistry, 25(2), 219–226. https://doi.org/10.1016/j.jnutbio.2013.10.010
  • Cabrera, D., Ruiz, A., Cabello-Verrugio, C., Brandan, E., Estrada, L., Pizarro, M., Solis, N., Torres, J., Barrera, F., & Arrese, M. (2016). Diet-Induced Nonalcoholic Fatty LiverDisease Is Associated with Sarcopenia and Decreased Serum Insulin-Like Growth Factor-1. Digestive Diseases and Sciences, 61(11), 3190–3198. https://doi.org/10.1007/s10620-016-4285-0
  • Challa, T. D., Wueest, S., Lucchini, F. C., Dedual, M., Modica, S., Borsigova, M., Wolfrum, C., Blüher, M., & Konrad, D. (2019). Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis. EMBO molecular medicine, 11(10), e10124. https://doi.org/10.15252/emmm.201810124
  • Dallio, M., Sangineto, M., Romeo, M., Villani, R., Romano, A. D., Loguercio, C., Serviddio, G., & Federico, A. (2021). Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression.International Journal of Molecular Sciences, 22(1), 436. https://doi.org/10.3390/ijms22010436
  • Diehl, A. M., & Day, C. (2017). Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. The New England journal of medicine, 377(21), 2063–2072.                      https://doi.org/10.1056/NEJMra1503519.
  • DiNicolantonio, J. J., Mehta, V., Onkaramurthy, N., & O’Keefe, J. H. (2018). Fructose-inducedinflammation and increased cortisol: A new mechanism for how sugar induces visceral adiposity. Progress in cardiovascular diseases, 61(1), 3–9. https://doi.org/10.1016/j.pcad.2017.12.001
  • Fabbrini, E., Serafini, M., Colic Baric, I., Hazen, S. L., & Klein, S. (2014). Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects.   Diabetes, 63(3), 976–981.           https://doi.org/10.2337/db13-1396
  • Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J. (2018). Mechanisms of NAFLD development and therapeutic strategies. Nature medicine, 24(7), 908 -922.https://doi.org/10.1038/s41591-018-0104-9
  • Grant, L. M., & Lisker-Melman, M. (2004). Nonalcoholic fatty liver disease. Annals of hepatology, 3(3), 93–99.
  • Harrison, S. A., Goodman, Z., Jabbar, A., Vemulapalli, R., Younes, Z. H., Freilich, B., Sheikh, M. Y., Schattenberg, J. M., Kayali, Z., Zivony, A., Sheikh, A., Garcia-Samaniego, J., Satapathy, S. K., Therapondos, G., Mena, E., Schuppan, D., Robinson, J., Chan, J. L., Hagerty, D. T., & Sanyal, A. J. (2020). A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. Journal of hepatology, 72(5), 816–827. https://doi.org/10.1016/j.jhep.2019.11.024
  • Hong, S. H., Ahmadian, M., Yu, R. T., Atkins, A. R., Downes, M., & Evans, R. M. (2014). Nuclear receptors and metabolism: from feast to famine. Diabetologia, 57(5), 860–867.https://doi.org/10.1007/s00125-014-3209-9
  • Jang, C., Hui, S., Lu, W., Cowan, A. J., Morscher, R. J., Lee, G., Liu, W., Tesz, G. J., Birnbaum, M. J., & Rabinowitz, J. D. (2018). The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. Cell metabolism, 27(2), 351–361.e3. https://doi.org/10.1016/j.cmet.2017.12.016
  • Jang, C., Wada, S., Yang, S., Gosis, B., Zeng, X., Zhang, Z., Shen, Y., Lee, G., Arany, Z., & Rabinowitz, J. D. (2020). The small intestine shields the liver from fructose-induced steatosis. Nature metabolism, 2(7), 586–593.    https://doi.org/10.1038/s42255-020-0222-9
  • Jegatheesan, P., & De Bandt, J. P. (2017). Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism. Nutrients, 9(3), 230. https://doi.org/10.3390/nu9030230
  • Jegatheesan, P., Beutheu, S., Ventura, G., Nubret, E., Sarfati, G., Bergheim, I., & De Bandt, J. P. (2015). Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats. The Journal of Nutrition, 145(10), 2273–2279. https://doi.org/10.3945/jn.115.218982
  • Jiang, S., Yan, C., Fang, Q. C., Shao, M. L., Zhang, Y. L., Liu, Y., Deng, Y. P., Shan, B., Liu, J. Q., Li, H. T., Yang, L., Zhou, J., Dai, Z., Liu, Y., & Jia, W. P. (2014). Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. The Journal of biological chemistry, 289(43), 29751–29765. https://doi.org/10.1074/jbc.M114.565960Kelly N., DNP, AGPCNP-BC.
  • Julia Wattacheril, MD, MPH. (2019). Non-alcoholic Fatty Liver Disease: Evidence-Based Management and Early Recognition of Non-alcoholic Steatohepatitis. The Journal for Nurse Practitioners
  • Kleiner, D. E., Brunt, E. M., Wilson, L. A., Behling, C., Guy, C., Contos, M., Cummings, O., Yeh, M., Gill, R., Chalasani, N., Neuschwander-Tetri, B. A., Diehl, A. M., Dasarathy, S.,Terrault, N., Kowdley, K., Loomba, R., Belt, P., Tonascia, J., Lavine, J. E., anyal, A. J.,Nonalcoholic Steatohepatitis Clinical Research Network (2019). Association of Histologic Disease Activity with Progression of Nonalcoholic Fatty Liver Disease. JAMA networkopen, 2(10), e1912565. https://doi.org/10.1001/jamanetworkopen.2019.12565
  • Krenkel, O., Puengel, T., Govaere, O., Abdallah, A. T., Mossanen, J. C., Kohlhepp, M., Liepelt, A., Lefebvre, E., Luedde, T., Hellerbrand, C., Weiskirchen, R., Longerich, T., Costa, I. G., Anstee, Q. M., Trautwein, C., & Tacke, F. (2018). Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology (Baltimore, Md.), 67(4), 1270–1283. https://doi.org/10.1002/hep.29544
  • Lefere, S., Devisscher, L., & Tacke, F. (2020). Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: Opportunities and challenges. Expert Opinion on Investigational Drugs, 29(2), 89–92. https://doi.org/10.1080/13543784.2020.1718106
  • Liu, J., Xu, Y., Hu, Y., & Wang, G. (2015). The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism: clinical and experimental, 64(3), 380–390. https://doi.org/10.1016/j.metabol.2014.11.009
  • Newsome, P. N., Buchholtz, K., Cusi, K., Linder, M., Okanoue, T., Ratziu, V., Sanyal, A. J., Sejling, A. S., Harrison, S. A., & NN9931-4296 Investigators. (2021). A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. The New England journal of medicine, 384(12),1113–1124. ttps://doi.org/10.1056/NEJMoa2028395Newsome, P., Francque, S., Harrison, S., Ratziu, V., Van Gaal, L., Calanna, S., Hansen, M., Linder, M., & Sanyal, A. (2019). Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Alimentary pharmacology & therapeutics, 50(2), 193–203.https://doi.org/10.1111/apt.15316
  • Nigro, D., Menotti, F., Cento, A. S., Serpe, L., Chiazza, F., Dal Bello, F., Romaniello, F., Medana, C., Collino, M., Aragno, M., & Mastrocola, R. (2017). Chronic administration of saturated fats and fructose differently affect SREBP activity resulting in different modulation of Nrf2 and Nlrp3 inflammasome pathways in mice liver. The Journal of Nutritional Biochemistry, 42, 160–171. https://doi.org/10.1016/j.jnutbio.2017.01.010
  • Nomura, K., & Yamanouchi, T. (2012). The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. The Journal of Nutritional Biochemistry, 23(3), 203–208. https://doi.org/10.1016/j.jnutbio.2011.09.006.
  • Pearson, S., Kietsiriroje, N., & Ajjan, R. A. (2019). Oral Semaglutide in the Management of Type 2 Diabetes: A Report on the Evidence to Date. Diabetes, metabolic syndrome and obesity: targets and therapy, 12, 2515-2529. https://doi.org/10.2147/DMSO.S229802
  • Peng, C., Stewart, A. G., Woodman, O. L., Ritchie, R. H., & Qin, C. X. (2020). Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments. Frontiers in Pharmacology, 11, 603926. https://doi.org/10.3389/fphar.2020.603926
  • Rao, Y., Xu, Z., Hu, Y. T., Li, C., Xu, Y. H., Song, Q. Q., Yu, H., Song, B. B., Chen, S. B. Li, Q. J., Huang, S. L., Tan, J. H., Ou, T. M., Wang, H. G.,     Zhong, G. P., Ye, J. M., & Huang, Z. S. (2020). Discovery of a promising agent IQZ23 for the treatment of obesity and related metabolic disorders. European journal of medicinal chemistry, 192, 112172. https://doi.org/10.1016/j.ejmech.2020.112172
  • Roeb, E., & Weiskirchen, R. (2021). Fructose and Non-Alcoholic Steatohepatitis. Frontiers in Pharmacology, 12, 634344. https://doi.org/10.3389/fphar.2021.634344
  • Sanders, F. W., & Griffin, J. L. (2016). De novo lipogenesis in the liver in health and disease: More than just a shunting yard for glucose. Biological reviews of the Cambridge Philosophical Society, 91(2), 452–468. https://doi.org/10.1111/brv.12178
  • Skenderian, S., Park, G., & Jang, C. (2020). Organismal Fructose Metabolism in Health and Non-Alcoholic Fatty Liver Disease. Biology, 9(11), 405. https://doi.org/10.3390/biology9110405
  • Softic, S., Cohen, D. E., & Kahn, C. R. (2016). Role of Dietary Fructose and Hepatic De-Novo Lipogenesis in Fatty Liver Disease. Digestive diseases and sciences, 61(5), 1282–1293. https://doi.org/10.1007/s10620-016-4054-0
  • Stephens, F. B., Chee, C., Wall, B. T., Murton, A. J., Shannon, C. E., van Loon, L.J., &Tsintzas, K. (2015). Lipid-induced insulin resistance is associated with an impaired skeletal muscle protein synthetic response to amino acid ingestion in healthy young men. Diabetes, 64(5), 1615–1620. https://doi.org/10.2337/db14-0961
  • Sun, X., Duan, X., Wang, C., Liu, Z., Sun, P., Huo, X., Ma, X., Sun, H., Liu, K., & Meng Q. (2017). Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice. European journal of pharmacology, 806, 75–82. https://doi.org/10.1016/j.ejphar.2017.04.021
  • Than, N. N., & Newsome, P. N. (2015). A concise review of non-alcoholic fatty liver disease. Atherosclerosis, 239(1), 192–202. https://doi.org/10.1016/j.atherosclerosis.2015.01.001
  • Theytaz, F., de Giorgi, S., Hodson, L., Stefanoni, N., Rey, V., Schneiter, P., Giusti, V., & Tappy, L. (2014). Metabolic fate of fructose ingested with and without glucose in a mixed meal. Nutrients, 6(7), 2632–2649. https://doi.org/10.3390/nu6072632
  • Vancells Lujan, P., Viñas Esmel, E., & Sacanella Meseguer, E. (2021). Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in its Development. Nutrients, 13(5), 1442. https://doi.org/10.3390/nu13051442
  • Wan, X., Xu, C., Yu, C., & Li, Y. (2016). Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH. Canadian Journal of Gastroenterology & Hepatology, 2016, 6489012. https://doi.org/10.1155/2016/6489012
  • Wong, V. W., Chan, W. K., Chitturi, S., Chawla, Y., Dan, Y. Y., Duseja, A., Fan, J., Goh, K. L.,Hamaguchi, M., Hashimoto, E., Kim, S. U., Lesmana, L. A., Lin, Y. C., Liu, C. J., Ni, Y. H., Sollano, J., Wong, S. K.,Wong, G. L., Chan, H. L., & Farrell, G. (2018). Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 1: Definition, risk factors and assessment. Journal of Gastroenterology and Herpetology, 33(1), 70–85. 100.
  • Zhang, S., Wong, Y. T., Tang, K. Y., Kwan, H. Y., & Su, T. (2020). Chinese Medicinal Herbs Targeting the Gut-Liver Axis and Adipose Tissue-Liver Axis for Non-Alcoholic Fatty Liver, Disease Treatments: The Ancient Wisdom and Modern Science. Frontiers in Endocrinology, 11,  572-729. https://doi.org/10.3389/fendo.2020.572729