{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:36:01Z","timestamp":1792704961286,"version":"4.5.0"},"reference-count":132,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) represents the result of hepatic fat overload not due to alcohol consumption and potentially evolving to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Fructose is a naturally occurring simple sugar widely used in food industry linked to glucose to form sucrose, largely contained in hypercaloric food and beverages. An increasing amount of evidence in scientific literature highlighted a detrimental effect of dietary fructose consumption on metabolic disorders such as insulin resistance, obesity, hepatic steatosis, and NAFLD-related fibrosis as well. An excessive fructose consumption has been associated with NAFLD development and progression to more clinically severe phenotypes by exerting various toxic effects, including increased fatty acid production, oxidative stress, and worsening insulin resistance. Furthermore, some studies in this context demonstrated even a crucial role in liver cancer progression. Despite this compelling evidence, the molecular mechanisms by which fructose elicits those effects on liver metabolism remain unclear. Emerging data suggest that dietary fructose may directly alter the expression of genes involved in lipid metabolism, including those that increase hepatic fat accumulation or reduce hepatic fat removal. This review aimed to summarize the current understanding of fructose metabolism on NAFLD pathogenesis and progression.<\/jats:p>","DOI":"10.3390\/nu13041314","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T06:35:53Z","timestamp":1618814153000},"page":"1314","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["The Role of Fructose in Non-Alcoholic Steatohepatitis: Old Relationship and New Insights"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0885-0793","authenticated-orcid":false,"given":"Alessandro","family":"Federico","sequence":"first","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3584-2414","authenticated-orcid":false,"given":"Valerio","family":"Rosato","sequence":"additional","affiliation":[{"name":"Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, \u201cScuola Medica Salernitana\u201d, University of Salerno, 84084 Salerno, Italy"},{"name":"Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0550-8201","authenticated-orcid":false,"given":"Mario","family":"Masarone","sequence":"additional","affiliation":[{"name":"Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, \u201cScuola Medica Salernitana\u201d, University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-5305","authenticated-orcid":false,"given":"Pietro","family":"Torre","sequence":"additional","affiliation":[{"name":"Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, \u201cScuola Medica Salernitana\u201d, University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4153-815X","authenticated-orcid":false,"given":"Marcello","family":"Dallio","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2970-9019","authenticated-orcid":false,"given":"Mario","family":"Romeo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Persico","sequence":"additional","affiliation":[{"name":"Internal Medicine and Hepatology Division, Department of Medicine, Surgery and Odontostomatology, \u201cScuola Medica Salernitana\u201d, University of Salerno, 84084 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1172\/JCI96702","article-title":"Fructose metabolism and metabolic disease","volume":"128","author":"Hannou","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_2","first-page":"294","article-title":"Adverse effects of dietary fructose","volume":"10","author":"Gaby","year":"2005","journal-title":"Altern. Med. Rev. J. Clin. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.amepre.2004.05.005","article-title":"Changes in beverage intake between 1977 and 2001","volume":"27","author":"Nielsen","year":"2004","journal-title":"Am. J. Prev. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.3945\/ajcn.112.057943","article-title":"Trends in sugar-sweetened beverage consumption among youth and adults in the United States: 1999\u20132010","volume":"98","author":"Kit","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1161\/CIRCULATIONAHA.115.018704","article-title":"Sugar-Sweetened Beverage Consumption Is Associated with Change of Visceral Adipose Tissue Over 6 Years of Follow-Up","volume":"133","author":"Ma","year":"2016","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3945\/ajcn.111.022533","article-title":"Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: A 6-mo randomized intervention study","volume":"95","author":"Maersk","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1001\/jama.287.18.2414","article-title":"The Glycemic Index","volume":"287","author":"Ludwig","year":"2002","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1172\/JCI37385","article-title":"Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight\/obese humans","volume":"119","author":"Stanhope","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_9","first-page":"503","article-title":"Association of fructose consumption and components of metabolic syndrome in human studies: A systematic review and meta-analysis","volume":"30","author":"Kelishadi","year":"2014","journal-title":"Nutrients"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1228S","DOI":"10.3945\/jn.108.098277","article-title":"National Estimates of Dietary Fructose Intake Increased from 1977 to 2004 in the United States","volume":"139","author":"Marriott","year":"2009","journal-title":"J. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.3945\/ajcn.114.100461","article-title":"A dose-response study of consuming high-fructose corn syrup\u2013sweetened beverages on lipid\/lipoprotein risk factors for cardiovascular disease in young adults","volume":"101","author":"Stanhope","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/j.metabol.2011.04.001","article-title":"The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: A randomized controlled trial","volume":"60","author":"Madero","year":"2011","journal-title":"Metabolism"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/MCO.0b013e328361c4d1","article-title":"Carbohydrate intake and nonalcoholic fatty liver disease","volume":"16","year":"2013","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1210\/er.2008-0033","article-title":"Hypothesis: Could Excessive Fructose Intake and Uric Acid Cause Type 2 Diabetes?","volume":"30","author":"Johnson","year":"2009","journal-title":"Endocr. Rev."},{"key":"ref_15","first-page":"4731","article-title":"The epidemiology of non-alcoholic fatty liver disease and its connection with cardiovascular disease: Role of endothelial dysfunction","volume":"20","author":"Federico","year":"2016","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.jhep.2013.05.044","article-title":"From NAFLD in clinical practice to answers from guidelines","volume":"59","author":"Nascimbeni","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: A multisystem disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1912565","DOI":"10.1001\/jamanetworkopen.2019.12565","article-title":"Association of Histologic Disease Activity with Progression of Nonalcoholic Fatty Liver Disease","volume":"2","author":"Kleiner","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.3748\/wjg.v18.i19.2300","article-title":"Animal models of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"18","author":"Takahashi","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.jhep.2008.02.011","article-title":"Fructose consumption as a risk factor for non-alcoholic fatty liver disease","volume":"48","author":"Ouyang","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1002\/hep.23535","article-title":"Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease","volume":"51","author":"Abdelmalek","year":"2010","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.jhep.2016.12.025","article-title":"Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents","volume":"66","author":"Mosca","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1002\/hep.30908","article-title":"Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation","volume":"71","author":"Chen","year":"2020","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Denkmayr, L., Feldman, A., Stechemesser, L., Eder, S.K., Zandanell, S., Schranz, M., Strasser, M., Huber-Sch\u00f6nauer, U., Buch, S., and Hampe, J. (2018). Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients. J. Clin. Med., 7.","DOI":"10.3390\/jcm7120562"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1155\/2008\/810961","article-title":"Soft Drink Consumption Linked with Fatty Liver in the Absence of Traditional Risk Factors","volume":"22","author":"Assy","year":"2008","journal-title":"Can. J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.jhep.2009.05.033","article-title":"Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome","volume":"51","author":"Abid","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/cphy.c130024","article-title":"Energy Metabolism in the Liver","volume":"4","author":"Rui","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1113\/jphysiol.2003.049247","article-title":"Simple-sugar meals target GLUT2 at enterocyte apical membranes to improve sugar absorption: A study in GLUT2-null mice","volume":"552","author":"Gouyon","year":"2003","journal-title":"J. Physiol."},{"key":"ref_29","first-page":"721","article-title":"Conversion of fructose to glucose in the rabbit small intestine. A reappraisal of the direct pathway","volume":"213","author":"Bismut","year":"1993","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R499","DOI":"10.1152\/ajpregu.00128.2015","article-title":"Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK","volume":"309","author":"Patel","year":"2015","journal-title":"Am. J. Physiol. Integr. Comp. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e18313","DOI":"10.7554\/eLife.18313","article-title":"Diabetes regulates fructose absorption through thioredoxin-interacting protein","volume":"5","author":"Dotimas","year":"2016","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1172\/jci.insight.96703","article-title":"Intestinal, but not hepatic, ChREBP is required for fructose tolerance","volume":"2","author":"Kim","year":"2017","journal-title":"JCI Insight"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nier, A., Brandt, A., Conzelmann, I.B., \u00d6zel, Y., and Bergheim, I. (2018). Non-Alcoholic Fatty Liver Disease in Overweight Children: Role of Fructose Intake and Dietary Pattern. Nutrients, 10.","DOI":"10.3390\/nu10091329"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10989","DOI":"10.1074\/jbc.M113.527002","article-title":"Glucose Transporter 8 (GLUT8) Mediates Fructose-induced de Novo Lipogenesis and Macrosteatosis","volume":"289","author":"DeBosch","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.clinre.2012.06.005","article-title":"Does fructose consumption contribute to non-alcoholic fatty liver disease?","volume":"36","author":"Tappy","year":"2012","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1369\/jhc.2009.953190","article-title":"Ketohexokinase: Expression and Localization of the Principal Fructose-metabolizing Enzyme","volume":"57","author":"Diggle","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4320","DOI":"10.1073\/pnas.1119908109","article-title":"Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice","volume":"109","author":"Ishimoto","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Geidl-Flueck, B., and Gerber, P.A. (2017). Insights into the Hexose Liver Metabolism\u2014Glucose versus Fructose. Nutrients, 9.","DOI":"10.3390\/nu9091026"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0885-4505(89)90011-X","article-title":"The glucose-6-phosphatase\/glucokinase ratio in the liver of obese-diabetic subjects","volume":"41","author":"Belfiore","year":"1989","journal-title":"Biochem. Med. Metab. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"729","DOI":"10.3945\/an.114.008144","article-title":"Health Implications of High-Fructose Intake and Current Research","volume":"6","author":"Dornas","year":"2015","journal-title":"Adv. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ymgme.2015.01.001","article-title":"Aldolase-B knockout in mice phenocopies hereditary fructose intolerance in humans","volume":"114","author":"Oppelt","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Skenderian, S., Park, G., and Jang, C. (2020). Organismal Fructose Metabolism in Health and Non-Alcoholic Fatty Liver Disease. Biology, 9.","DOI":"10.3390\/biology9110405"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/dmrr.488","article-title":"Fructose-mediated non-enzymatic glycation: Sweet coupling or bad modification","volume":"20","author":"Schalkwijk","year":"2004","journal-title":"Diabetes\/Metab. Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.2337\/db16-0682","article-title":"Diabetic Cardiomyopathy: The Case for a Role of Fructose in Disease Etiology","volume":"65","author":"Delbridge","year":"2016","journal-title":"Diabetes"},{"key":"ref_45","first-page":"E25","article-title":"Chronic fructose renders pancreatic \u03b2-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling","volume":"317","author":"Bartley","year":"2019","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/jn\/111.2.307","article-title":"Long-Term Effects of Moderate Fructose Feeding on Glucose Tolerance Parameters in Rats","volume":"111","author":"Blakely","year":"1981","journal-title":"J. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.3945\/ajcn.116.137786","article-title":"Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: A systematic review and meta-analysis of diet-intervention trials","volume":"104","author":"Schene","year":"2016","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/nm.4350","article-title":"Insulin action and resistance in obesity and type 2 diabetes","volume":"23","author":"Czech","year":"2017","journal-title":"Nat. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.diabet.2010.03.003","article-title":"Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men","volume":"36","author":"Sobrecases","year":"2010","journal-title":"Diabetes Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1210\/jc.2010-2007","article-title":"A Dual Sugar Challenge Test for Lipogenic Sensitivity to Dietary Fructose","volume":"96","author":"Hudgins","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.tem.2016.06.005","article-title":"The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis","volume":"27","author":"Herman","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cmet.2012.05.002","article-title":"Hepatic Insulin Signaling Is Required for Obesity-Dependent Expression of SREBP-1c mRNA but Not for Feeding-Dependent Expression","volume":"15","author":"Haas","year":"2012","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1172\/JCI41636","article-title":"The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans","volume":"122","author":"Benhamed","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4372","DOI":"10.1172\/JCI81993","article-title":"ChREBP regulates fructose-induced glucose production independently of insulin signaling","volume":"126","author":"Kim","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.bbrc.2009.09.109","article-title":"Replacing dietary glucose with fructose increases ChREBP activity and SREBP-1 protein in rat liver nucleus","volume":"390","author":"Koo","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1210\/en.2012-1725","article-title":"The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats","volume":"154","author":"Erion","year":"2013","journal-title":"Endocrinology"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Iizuka, K. (2017). The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism. Nutrients, 9.","DOI":"10.3390\/nu9020181"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1016\/j.febslet.2009.07.053","article-title":"Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes","volume":"583","author":"Iizuka","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cmet.2015.12.003","article-title":"FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver","volume":"23","author":"BonDurant","year":"2016","journal-title":"Cell Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1093\/jn\/130.6.1531","article-title":"A High Fructose Diet Affects the Early Steps of Insulin Action in Muscle and Liver of Rats","volume":"130","author":"Bezerra","year":"2000","journal-title":"J. Nutr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jnutbio.2013.10.014","article-title":"Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats","volume":"25","author":"Rebollo","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Jegatheesan, P., and De Bandt, J. (2017). Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism. Nutrients, 9.","DOI":"10.3390\/nu9030230"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.nbd.2016.02.005","article-title":"High-fructose intake as risk factor for neurodegeneration: Key role for carboxy methyllysine accumulation in mice hippocampal neurons","volume":"89","author":"Mastrocola","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_64","first-page":"23","article-title":"Methylglyoxal, the dark side of glycolysis","volume":"9","author":"Eallaman","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1743-7075-10-32","article-title":"Fructose-induced stress signaling in the liver involves methylglyoxal","volume":"10","author":"Wei","year":"2013","journal-title":"Nutr. Metab."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Lanaspa, M.A., Cicerchi, C., Garcia, G., Li, N., Roncal-Jimenez, C.A., Rivard, C.J., Hunter, B., Andr\u00e9s-Hernando, A., Ishimoto, T., and S\u00e1nchez-Lozada, L.G. (2012). Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048801"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1001\/jama.2010.1638","article-title":"Fructose-Rich Beverages and Risk of Gout in Women","volume":"304","author":"Choi","year":"2010","journal-title":"JAMA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"40732","DOI":"10.1074\/jbc.M112.399899","article-title":"Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress: Potential Role in Fructose-Dependent and- Independent Fatty Liver","volume":"287","author":"Lanaspa","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"9547613","DOI":"10.1155\/2018\/9547613","article-title":"Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease","volume":"2018","author":"Masarone","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/labinvest.2014.98","article-title":"Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes","volume":"94","author":"Choi","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"C584","DOI":"10.1152\/ajpcell.00600.2006","article-title":"Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative\/nitrosative stress","volume":"293","author":"Sautin","year":"2007","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.bbrc.2014.04.080","article-title":"High uric acid directly inhibits insulin signalling and induces insulin resistance","volume":"447","author":"Zhu","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.3748\/wjg.v20.i7.1768","article-title":"Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease","volume":"20","author":"Zhang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1051\/medsci\/2007233291","article-title":"La r\u00e9ponse UPR","volume":"23","author":"Foufelle","year":"2007","journal-title":"M\u00e9decine\/Sciences"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.jhep.2010.11.005","article-title":"Endoplasmic reticulum stress in liver disease","volume":"54","author":"Malhi","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.26594","article-title":"High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase","volume":"58","author":"Ishimoto","year":"2013","journal-title":"Hepatology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jhep.2009.03.008","article-title":"Kupffer cells in non-alcoholic fatty liver disease: The emerging view","volume":"51","author":"Baffy","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6489012","DOI":"10.1155\/2016\/6489012","article-title":"Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH","volume":"2016","author":"Wan","year":"2016","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Dallio, M., Sangineto, M., Romeo, M., Villani, R., Romano, A.D., Loguercio, C., Serviddio, G., and Federico, A. (2021). Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010436"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"8603164","DOI":"10.1155\/2016\/8603164","article-title":"Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis","volume":"2016","author":"Kushiyama","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.tips.2013.03.007","article-title":"Oxidative stress in vascular disease and its pharmacological prevention","volume":"34","author":"Li","year":"2013","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.pcad.2017.12.001","article-title":"Fructose-induced inflammation and increased cortisol: A new mechanism for how sugar induces visceral adiposity","volume":"61","author":"DiNicolantonio","year":"2018","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1021\/bi015803t","article-title":"11\u03b2-Hydroxysteroid Dehydrogenase Type 1 from Human Liver: Dimerization and Enzyme Cooperativity Support Its Postulated Role as Glucocorticoid Reductase","volume":"41","author":"Maser","year":"2002","journal-title":"Biochemistry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.1210\/en.2012-1562","article-title":"Sugar Making Sugar: Gluconeogenesis Triggered by Fructose via a Hypothalamic-Adrenal-Corticosterone Circuit","volume":"153","author":"Cawley","year":"2012","journal-title":"Endocrinology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.jnutbio.2009.05.006","article-title":"Dietary fructose and intestinal barrier: Potential risk factor in the pathogenesis of nonalcoholic fatty liver disease","volume":"20","author":"Spruss","year":"2009","journal-title":"J. Nutr. Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.cmet.2017.12.016","article-title":"The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids","volume":"27","author":"Jang","year":"2018","journal-title":"Cell Metab."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s42255-020-0222-9","article-title":"The small intestine shields the liver from fructose-induced steatosis","volume":"2","author":"Jang","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/hep.27149","article-title":"Hypercaloric diets with increased meal frequency, but not meal size, increase intrahepatic triglycerides: A randomized controlled trial","volume":"60","author":"Koopman","year":"2014","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrgastro.2016.85","article-title":"The role of the gut microbiota in NAFLD","volume":"13","author":"Leung","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3389\/fgene.2018.00203","article-title":"High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring","volume":"9","author":"Astbury","year":"2018","journal-title":"Front. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"770","DOI":"10.3945\/jn.116.242859","article-title":"Intestinal Barrier Function and the Gut Microbiome Are Differentially Affected in Mice Fed a Western-Style Diet or Drinking Water Supplemented with Fructose","volume":"147","author":"Volynets","year":"2017","journal-title":"J. Nutr."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.clnu.2015.01.021","article-title":"Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease","volume":"35","author":"Jegatheesan","year":"2016","journal-title":"Clin. Nutr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000447252","article-title":"Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?","volume":"1","author":"Fukui","year":"2016","journal-title":"Inflamm. Intest. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"560620","DOI":"10.1155\/2014\/560620","article-title":"Fructose Induced Endotoxemia in Pediatric Nonalcoholic Fatty Liver Disease","volume":"2014","author":"Jin","year":"2014","journal-title":"Int. J. Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3945\/ajcn.112.057331","article-title":"Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates","volume":"98","author":"Kavanagh","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.3389\/fimmu.2017.01159","article-title":"Fructose: A Dietary Sugar in Crosstalk with Microbiota Contributing to the Development and Progression of Non-Alcoholic Liver Disease","volume":"8","author":"Lambertz","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1053\/j.gastro.2016.06.022","article-title":"Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol","volume":"151","author":"Rahman","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.jnutbio.2015.05.011","article-title":"Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time","volume":"26","author":"Sellmann","year":"2015","journal-title":"J. Nutr. Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1016\/j.jada.2005.07.002","article-title":"Fructose Intake at Current Levels in the United States May Cause Gastrointestinal Distress in Normal Adults","volume":"105","author":"Beyer","year":"2005","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.cgh.2013.02.015","article-title":"Fecal Microbiome and Volatile Organic Compound Metabolome in Obese Humans with Nonalcoholic Fatty Liver Disease","volume":"11","author":"Raman","year":"2013","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_101","first-page":"255","article-title":"The evolution of cooperation within the gut microbiota","volume":"533","author":"Foster","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"563","DOI":"10.3389\/fmicb.2017.00563","article-title":"Gut Microbiota Modulation and Its Relationship with Obesity Using Prebiotic Fibers and Probiotics: A Review","volume":"8","author":"Dahiya","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_103","first-page":"1027","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7353642","DOI":"10.1155\/2016\/7353642","article-title":"Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature","volume":"2016","author":"Khan","year":"2016","journal-title":"J. Obes."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Di Luccia, B., Crescenzo, R., Mazzoli, A., Cigliano, L., Venditti, P., Walser, J.-C., Widmer, A., Baccigalupi, L., Ricca, E., and Iossa, S. (2015). Rescue of Fructose-Induced Metabolic Syndrome by Antibiotics or Faecal Transplantation in a Rat Model of Obesity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134893"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/oby.2009.167","article-title":"Microbiota and SCFA in Lean and Overweight Healthy Subjects","volume":"18","author":"Schwiertz","year":"2010","journal-title":"Obesity"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1080\/19490976.2019.1592420","article-title":"High intake of dietary fructose in overweight\/obese teenagers associated with depletion of Eubacterium and Streptococcus in gut microbiome","volume":"10","author":"Jones","year":"2019","journal-title":"Gut Microbes"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrendo.2015.128","article-title":"Short-chain fatty acids in control of body weight and insulin sensitivity","volume":"11","author":"Canfora","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Endo, H., Niioka, M., Kobayashi, N., Tanaka, M., and Watanabe, T. (2013). Butyrate-Producing Probiotics Reduce Nonalcoholic Fatty Liver Disease Progression in Rats: New Insight into the Probiotics for the Gut-Liver Axis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063388"},{"key":"ref_110","first-page":"586","article-title":"Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate","volume":"579","author":"Zhao","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.2337\/dc10-0856","article-title":"Effect of a 12-Month Intensive Lifestyle Intervention on Hepatic Steatosis in Adults with Type 2 Diabetes","volume":"33","author":"Lazo","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/hep.23276","article-title":"Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis","volume":"51","author":"Promrat","year":"2010","journal-title":"Hepatology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.2337\/db12-1651","article-title":"Exercise Prevents Fructose-Induced Hypertriglyceridemia in Healthy Young Subjects","volume":"62","author":"Egli","year":"2013","journal-title":"Diabetes"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jnutbio.2018.02.003","article-title":"Fructose liquid and solid formulations differently affect gut integrity, microbiota composition and related liver toxicity: A comparative in vivo study","volume":"55","author":"Mastrocola","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1159\/000341631","article-title":"Intake of Liquid and Solid Sucrose in Relation to Changes in Body Fatness over 6 Years among 8- to 10-Year-Old Children: The European Youth Heart Study","volume":"5","author":"Olsen","year":"2012","journal-title":"Obes. Facts"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.2337\/diabetes.52.9.2426","article-title":"Properties of Normal and Mutant Recombinant Human Ketohexokinases and Implications for the Pathogenesis of Essential Fructosuria","volume":"52","author":"Asipu","year":"2003","journal-title":"Diabetes"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1038\/ncomms3434","article-title":"Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome","volume":"4","author":"Lanaspa","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1021\/ml200070g","article-title":"Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site","volume":"2","author":"Maryanoff","year":"2011","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4762","DOI":"10.1016\/j.bmcl.2011.06.067","article-title":"Optimization of a pyrazole hit from FBDD into a novel series of indazoles as ketohexokinase inhibitors","volume":"21","author":"Zhang","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"7835","DOI":"10.1021\/acs.jmedchem.7b00947","article-title":"Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)","volume":"60","author":"Huard","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1172\/JCI134165","article-title":"Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease","volume":"130","author":"Smith","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.cmet.2017.07.009","article-title":"Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation","volume":"26","author":"Kim","year":"2017","journal-title":"Cell Metab."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Ritze, Y., B\u00e1rdos, G., Claus, A., Ehrmann, V., Bergheim, I., Schwiertz, A., and Bischoff, S.C. (2014). Lactobacillus rhamnosus GG Protects against Non-Alcoholic Fatty Liver Disease in Mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0080169"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Chen, Q., Wang, T., Li, J., Wang, S., Qiu, F., Yu, H., Zhang, Y., and Wang, T. (2017). Effects of Natural Products on Fructose-Induced Nonalcoholic Fatty Liver Disease (NAFLD). Nutrients, 9.","DOI":"10.3390\/nu9020096"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.jep.2016.09.050","article-title":"Symplocos cochinchinensis enhances insulin sensitivity via the down regulation of lipogenesis and insulin resistance in high energy diet rat model","volume":"193","author":"Antu","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ejphar.2014.01.038","article-title":"Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat","volume":"727","author":"Prakash","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1080\/13880209.2016.1187179","article-title":"Curcumin inhibits hyperlipidemia and hepatic fat accumulation in high-fructose-fed male Wistar rats","volume":"54","author":"Maithilikarpagaselvi","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1021\/acs.jafc.6b00290","article-title":"Isoorientin Prevents Hyperlipidemia and Liver Injury by Regulating Lipid Metabolism, Antioxidant Capability, and Inflammatory Cytokine Release in High-Fructose-Fed Mice","volume":"64","author":"Yuan","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.freeradbiomed.2014.04.011","article-title":"(\u2212)-Epicatechin mitigates high-fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress","volume":"72","author":"Bettaieb","year":"2014","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1007\/s00394-014-0765-1","article-title":"High-fructose corn syrup-induced hepatic dysfunction in rats: Improving effect of resveratrol","volume":"54","author":"Sadi","year":"2015","journal-title":"Eur. J. Nutr."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/labinvest.2012.75","article-title":"Metformin protects against the development of fructose-induced steatosis in mice: Role of the intestinal barrier function","volume":"92","author":"Spruss","year":"2012","journal-title":"Lab. Investig."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/4\/1314\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:48:45Z","timestamp":1760161725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/4\/1314"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,16]]},"references-count":132,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["nu13041314"],"URL":"https:\/\/doi.org\/10.3390\/nu13041314","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,16]]}}}