{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:19:47Z","timestamp":1793042387518,"version":"4.5.0"},"reference-count":166,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The emerging issues nowadays are non-alcoholic fatty liver disease (NAFLD) and its advanced stage non-alcoholic steatohepatitis (NASH), which further can be a predisposing factor for chronic liver complications, such as cirrhosis and\/or development of hepatocellular carcinoma (HCC). Liver lipotoxicity can influence the accumulation of reactive oxygen species (ROS), so oxidative stress is also crucial for the progression of NASH. Moreover, NASH is in strong connection with metabolic disorders, and supporting evidence shows that insulin resistance (IR) is in a close relation to NAFLD, as it is involved in the progression to NASH and further progression to hepatic fibrosis. The major issue is that, at the moment, NASH treatment is based on lifestyle changes only due to the fact that no approved therapeutic options are available. The development of new therapeutic strategies should be conducted towards the potential NAFLD and NASH treatment by the modulation of IR but also by dietary antioxidants. As it seems, NASH is going to be the leading indication for liver transplantation as a consequence of increased disease prevalence and the lack of approved treatment; thus, an effective solution is needed as soon as possible.<\/jats:p>","DOI":"10.3390\/ijms23095146","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T13:10:26Z","timestamp":1651756226000},"page":"5146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Lipotoxicity as the Leading Cause of Non-Alcoholic Steatohepatitis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9676-7198","authenticated-orcid":false,"given":"Marija","family":"Brankovi\u0107","sequence":"first","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Jovanovi\u0107","sequence":"additional","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Duki\u0107","sequence":"additional","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4694-5416","authenticated-orcid":false,"given":"Tijana","family":"Radonji\u0107","sequence":"additional","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Opri\u0107","sequence":"additional","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6040-0183","authenticated-orcid":false,"given":"Slobodan","family":"Kla\u0161nja","sequence":"additional","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Zdravkovi\u0107","sequence":"additional","affiliation":[{"name":"University Hospital Medical Center Be\u017eanijska kosa, Dr \u017dor\u017ea Matea bb, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1001\/jama.2020.2298","article-title":"Nonalcoholic Steatohepatitis","volume":"323","author":"Sheka","year":"2020","journal-title":"JAMA"},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/dom.14322","article-title":"Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review","volume":"23","author":"Cariou","year":"2021","journal-title":"Diabetes, Obes. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2016). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol., 64, 1388\u20131402.","DOI":"10.1016\/j.jhep.2015.11.004"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"274","DOI":"10.4254\/wjh.v6.i5.274","article-title":"Gender and racial differences in nonalcoholic fatty liver disease","volume":"6","author":"Pan","year":"2014","journal-title":"World J. Hepatol."},{"key":"ref_7","first-page":"320","article-title":"From the metabolic syndrome to NAFLD or vice versa?","volume":"42","author":"Vanni","year":"2010","journal-title":"Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity","volume":"116","author":"Matteoni","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/s41395-018-0088-6","article-title":"NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances","volume":"113","author":"Noureddin","year":"2018","journal-title":"Am. J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1053\/j.gastro.2010.09.038","article-title":"Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study","volume":"140","author":"Williams","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/hep.27368","article-title":"Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up","volume":"61","author":"Ekstedt","year":"2015","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.jhep.2012.11.021","article-title":"Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal","volume":"58","author":"Machado","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/hep.24452","article-title":"Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta-analysis","volume":"54","author":"Hernaez","year":"2011","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/hep.21496","article-title":"The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD","volume":"45","author":"Angulo","year":"2007","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/hep.21669","article-title":"FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest","volume":"46","author":"Mallet","year":"2007","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3109\/07853890.2010.518623","article-title":"Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity","volume":"43","author":"Musso","year":"2011","journal-title":"Ann. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/978-3-319-48382-5_19","article-title":"Non-Alcoholic Fatty Liver Disease","volume":"960","author":"Engin","year":"2017","journal-title":"Adv Exp Med Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R52","DOI":"10.1530\/EC-20-0490","article-title":"Pathophysiology of NASH in endocrine diseases","volume":"10","author":"Gariani","year":"2021","journal-title":"Endocr. Connect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1016\/j.jhep.2012.12.003","article-title":"A 360-degree overview of paediatric NAFLD: Recent insights","volume":"58","author":"Nobili","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"550","DOI":"10.4254\/wjh.v5.i10.550","article-title":"Lipotoxicity in the liver","volume":"5","author":"Kereszturi","year":"2013","journal-title":"World J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Fujii, H., Kawada, N., and Japan Study Group of NAFLD (JSG-NAFLD) (2020). The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113863"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1002\/hep.30429","article-title":"Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease","volume":"70","author":"Khan","year":"2019","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Armandi, A., Rosso, C., Caviglia, G., and Bugianesi, E. (2021). Insulin Resistance across the Spectrum of Nonalcoholic Fatty Liver Disease. Metabolites, 11.","DOI":"10.3390\/metabo11030155"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.freeradbiomed.2019.05.029","article-title":"Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease","volume":"144","author":"Pierantonelli","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jhep.2017.11.014","article-title":"Lipotoxicity and the gut-liver axis in NASH pathogenesis","volume":"68","author":"Marra","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.tem.2011.02.003","article-title":"Regulation of lipid droplets by autophagy","volume":"22","author":"Dong","year":"2011","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C776","DOI":"10.1152\/ajpcell.00507.2009","article-title":"Autophagy in health and disease. 1. Regulation and significance of autophagy: An overview","volume":"298","author":"Mehrpour","year":"2010","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/hep.21313","article-title":"Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob\/ob mice","volume":"44","author":"Colina","year":"2006","journal-title":"Hepatology"},{"key":"ref_29","first-page":"1287","article-title":"High-fat diet decreases activity of the oxidative phosphorylation complexes and causes nonalcoholic steatohepatitis in mice","volume":"7","author":"Grau","year":"2014","journal-title":"Dis. Model. Mech."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s00392-020-01709-7","article-title":"NAFLD and cardiovascular diseases: A clinical review","volume":"110","author":"Kasper","year":"2020","journal-title":"Clin. Res. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1055\/a-0784-8827","article-title":"Nonalcoholic steatohepatitis (NASH)\u2014Current treatment recommendations and future developments","volume":"57","author":"Roeb","year":"2019","journal-title":"Z. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/liv.14844","article-title":"New drugs for NASH","volume":"41","author":"Albhaisi","year":"2021","journal-title":"Liver Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1080\/13543784.2021.1951701","article-title":"Anti-diabetic drugs and NASH: From current options to promising perspectives","volume":"30","author":"Smati","year":"2021","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1194\/jlr.R066514","article-title":"Lipid signaling and lipotoxicity in metaflammation: Indications for metabolic disease pathogenesis and treatment","volume":"57","author":"Ertunc","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14859","DOI":"10.1038\/ncomms14859","article-title":"Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice","volume":"8","author":"Schweiger","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI23621","article-title":"Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.tem.2015.11.008","article-title":"The Role of Cholesterol in the Pathogenesis of NASH","volume":"27","author":"Ioannou","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1073\/pnas.1423952112","article-title":"Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids","volume":"112","author":"Vatner","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1007\/s00535-013-0758-5","article-title":"Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease","volume":"48","author":"Kawano","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1053\/j.gastro.2012.02.003","article-title":"Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications","volume":"142","author":"Cusi","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/hep.21655","article-title":"Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis","volume":"45","author":"Yamaguchi","year":"2007","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1586\/egh.09.32","article-title":"Lipotoxicity in nonalcoholic fatty liver disease: Not all lipids are created equal","volume":"3","author":"Alkhouri","year":"2009","journal-title":"Expert Rev. Gastroenterol Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/hep.25601","article-title":"Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice","volume":"56","author":"Fuchs","year":"2012","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1194\/jlr.R066357","article-title":"Lipotoxic lethal and sublethal stress signaling in hepatocytes: Relevance to NASH pathogenesis","volume":"57","author":"Hirsova","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1074\/jbc.M807616200","article-title":"Hepatic Lipid Partitioning and Liver Damage in Nonalcoholic Fatty Liver Disease: Role of stearoyl-CoA desaturase","volume":"284","author":"Li","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.jhep.2010.01.003","article-title":"Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis","volume":"52","author":"Akazawa","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14890","DOI":"10.1074\/jbc.M010286200","article-title":"Palmitate-induced Apoptosis Can Occur through a Ceramide-independent Pathway","volume":"276","author":"Listenberger","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.febslet.2010.01.046","article-title":"Intrahepatic cholesterol influences progression, inhibition and reversal of non-alcoholic steatohepatitis in hyperlipidemic mice","volume":"584","author":"Wouters","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nri3793","article-title":"Cholesterol, inflammation and innate immunity","volume":"15","author":"Tall","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cmet.2006.07.006","article-title":"Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis","volume":"4","author":"Mari","year":"2006","journal-title":"Cell Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0168-8278(02)00073-9","article-title":"In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases","volume":"37","author":"Seki","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.jhep.2017.01.022","article-title":"NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice","volume":"66","author":"Mridha","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/hep.26604","article-title":"Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice","volume":"59","author":"Tomita","year":"2014","journal-title":"Hepatology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.freeradbiomed.2017.01.023","article-title":"Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis","volume":"111","author":"Bellanti","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.tem.2012.04.005","article-title":"Role of ceramides in nonalcoholic fatty liver disease","volume":"23","author":"Pagadala","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1172\/JCI0216886","article-title":"Orchestrating the unfolded protein response in health and sease","volume":"110","author":"Kaufman","year":"2002","journal-title":"J. Clin. Invest."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.jhep.2017.04.026","article-title":"Biliary bile acids in hepatobiliary injury\u2014What is the link?","volume":"67","author":"Fickert","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1002\/hep.23810","article-title":"The biliary HCO3\u2212 umbrella: A unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies","volume":"52","author":"Beuers","year":"2010","journal-title":"Hepatology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1002\/hep.26225","article-title":"Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis","volume":"57","author":"Bechmann","year":"2013","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"R85","DOI":"10.1530\/JOE-15-0469","article-title":"The role of bile acids in metabolic regulation","volume":"228","author":"Haluzik","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.jhep.2018.06.008","article-title":"Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease","volume":"69","author":"Lebeaupin","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/sj.embor.7400779","article-title":"Mediators of endoplasmic reticulum stress-induced apoptosis","volume":"7","author":"Szegezdi","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1097\/TP.0000000000002480","article-title":"Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH","volume":"103","author":"Pierantonelli","year":"2019","journal-title":"Transplantation"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jhep.2011.05.019","article-title":"Lipotoxicity in NASH","volume":"56","author":"Fuchs","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1126\/science.287.5453.664","article-title":"Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1","volume":"287","author":"Urano","year":"2000","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"846","DOI":"10.2353\/ajpath.2006.050953","article-title":"A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats: Role of Peroxisome Proliferator-Activated Receptor-\u03b1 and n-3 Polyunsaturated Fatty Acid Treatment on Liver Injury","volume":"169","author":"Candelaresi","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.1123480","article-title":"Proapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1\u03b1","volume":"312","author":"Hetz","year":"2006","journal-title":"Science"},{"key":"ref_68","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_69","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1194\/jlr.R067595","article-title":"The role of ER stress in lipid metabolism and lipotoxicity","volume":"57","author":"Han","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nature09968","article-title":"Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity","volume":"473","author":"Fu","year":"2011","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1210\/en.2005-0570","article-title":"Saturated Fatty Acids Promote Endoplasmic Reticulum Stress and Liver Injury in Rats with Hepatic Steatosis","volume":"147","author":"Wang","year":"2006","journal-title":"Endocrinology"},{"key":"ref_72","first-page":"E1027","article-title":"Linking endoplasmic reticulum stress to cell death in hepatocytes: Roles of C\/EBP homologous protein and chemical chaperones in palmitate-mediated cell death","volume":"298","author":"Pfaffenbach","year":"2010","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/sj.onc.1210638","article-title":"Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis","volume":"27","author":"Deniaud","year":"2007","journal-title":"Oncogene"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.tem.2016.11.006","article-title":"Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies","volume":"28","author":"Sunny","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.cmet.2011.11.004","article-title":"Excessive Hepatic Mitochondrial TCA Cycle and Gluconeogenesis in Humans with Nonalcoholic Fatty Liver Disease","volume":"14","author":"Sunny","year":"2011","journal-title":"Cell Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1053\/j.gastro.2010.05.039","article-title":"Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals","volume":"139","author":"Iozzo","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_77","first-page":"E484","article-title":"Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity","volume":"310","author":"Patterson","year":"2016","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1126\/science.1104816","article-title":"Host-Bacterial Mutualism in the Human Intestine","volume":"307","author":"Ley","year":"2005","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Filipovic, B., Lukic, S., Mijac, D., Marjanovic-Haljilji, M., Vojnovic, M., Bogdanovic, J., Glisic, T., Filipovic, N., Al Kiswani, J., and Djokovic, A. (2021). The New Therapeutic Approaches in the Treatment of Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413219"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41575-018-0011-z","article-title":"The gut\u2013liver axis and the intersection with the microbiome","volume":"15","author":"Tripathi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nm.3893","article-title":"Inflammasomes: Mechanism of action, role in disease, and therapeutics","volume":"21","author":"Guo","year":"2015","journal-title":"Nat. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1053\/j.gastro.2008.10.080","article-title":"Microbes in Gastrointestinal Health and Disease","volume":"136","author":"Neish","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nrmicro2974","article-title":"The gut microbiota\u2014Masters of host development and physiology","volume":"11","author":"Sommer","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature05414","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"ref_85","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_86","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1194\/jlr.R036012","article-title":"The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism","volume":"54","author":"Groen","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.2337\/db07-1403","article-title":"Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet-Induced Obesity and Diabetes in Mice","volume":"57","author":"Cani","year":"2008","journal-title":"Diabetes"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.dld.2014.02.010","article-title":"Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity","volume":"46","author":"Giorgio","year":"2014","journal-title":"Dig. Liver Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7381","DOI":"10.3748\/wjg.v20.i23.7381","article-title":"Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease","volume":"20","author":"Miura","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_90","first-page":"G433","article-title":"Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice","volume":"300","author":"Csak","year":"2011","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.2337\/db06-1491","article-title":"Metabolic endotoxemia initiates obesity and insulin resistance","volume":"56","author":"Cani","year":"2007","journal-title":"Diabetes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nri.2017.7","article-title":"Dysbiosis and the immune system","volume":"17","author":"Levy","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Ji, Y., Yin, Y., Li, Z., and Zhang, W. (2019). Gut Microbiota-Derived Components and Metabolites in the Progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients, 11.","DOI":"10.3390\/nu11081712"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.2147\/DMSO.S249949","article-title":"Serum LPS and CD163 Biomarkers Confirming the Role of Gut Dysbiosis in Overweight Patients with NASH","volume":"13","author":"Hegazy","year":"2020","journal-title":"Diabetes, Metab. Syndr. Obesity: Targets Ther."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Du Plessis, J., Korf, H., Van Pelt, J., Windmolders, P., Vander Elst, I., Verrijken, A., Hubens, G., Van Gaal, L., Cassiman, D., and Nevens, F. (2016). Pro-Inflammatory Cytokines but Not Endotoxin-Related Parameters Associate with Disease Severity in Patients with NAFLD. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166048"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/hep.31056","article-title":"Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD","volume":"72","author":"Carpino","year":"2019","journal-title":"Hepatology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mam.2018.06.003","article-title":"Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications","volume":"65","author":"Weiskirchen","year":"2018","journal-title":"Mol. Asp. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrgastro.2015.200","article-title":"Immunology in the liver\u2014From homeostasis to disease","volume":"13","author":"Heymann","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/hepr.13493","article-title":"The stratification of cirrhosis","volume":"50","author":"Maurice","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1002\/hep.510300604","article-title":"Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis","volume":"30","author":"Angulo","year":"1999","journal-title":"Hepatology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/cld.721","article-title":"The Association Between Nonalcoholic Fatty Liver Disease and Cardiovascular Disease Outcomes","volume":"12","author":"Wong","year":"2018","journal-title":"Clin. Liver Dis."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Piazzolla, V.A., and Mangia, A. (2020). Noninvasive Diagnosis of NAFLD and NASH. Cells, 9.","DOI":"10.3390\/cells9041005"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/hep.20466","article-title":"Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity","volume":"40","author":"Browning","year":"2004","journal-title":"Hepatology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1111\/liv.12226","article-title":"Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD)","volume":"33","author":"Verma","year":"2013","journal-title":"Liver Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1002\/hep.22429","article-title":"Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes","volume":"48","author":"Fracanzani","year":"2008","journal-title":"Hepatology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/hep.27395","article-title":"The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease","volume":"61","author":"Maximos","year":"2015","journal-title":"Hepatology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1053\/jhep.2003.50229","article-title":"Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values","volume":"37","author":"Mofrad","year":"2003","journal-title":"Hepatology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/S1665-2681(19)31316-X","article-title":"Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: Introduction of CHA index","volume":"12","author":"Polyzos","year":"2013","journal-title":"Ann. Hepatol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cgh.2009.05.033","article-title":"Comparison of Noninvasive Markers of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease","volume":"7","author":"Shah","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_113","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_114","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/hep.27362","article-title":"Magnetic Resonance Elastography Predicts Advanced Fibrosis in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Study","volume":"60","author":"Loomba","year":"2014","journal-title":"Hepatology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1111\/apt.15503","article-title":"Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials","volume":"50","author":"Pai","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1002\/hep.20920","article-title":"Insulin resistance: A metabolic pathway to chronic liver disease","volume":"42","author":"Bugianesi","year":"2005","journal-title":"Hepatology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1002\/hep.510290632","article-title":"Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways","volume":"29","author":"Ridolfi","year":"1999","journal-title":"Hepatology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"71","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1177\/2047487319891783","article-title":"Non-alcoholic fatty liver disease, a new and growing risk indicator for cardiovascular disease","volume":"27","author":"Janssen","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1177\/2047487319869400","article-title":"Lifestyle factors and high-risk atherosclerosis: Pathways and mechanisms beyond traditional risk factors","volume":"27","author":"Lechner","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1161\/ATVBAHA.107.160192","article-title":"Overproduction of Very Low\u2013Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome","volume":"28","author":"Adiels","year":"2008","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41590-019-0548-1","article-title":"Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation","volume":"21","author":"Zewinger","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejphar.2016.04.024","article-title":"Mechanisms for the activation of Toll-like receptor 2\/4 by saturated fatty acids and inhibition by docosahexaenoic acid","volume":"785","author":"Hwang","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"S209","DOI":"10.1016\/j.dsx.2016.12.033","article-title":"Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: A systematic review and meta-analysis","volume":"11","author":"Haddad","year":"2017","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Osawa, K., Miyoshi, T., Yamauchi, K., Koyama, Y., Nakamura, K., Sato, S., Kanazawa, S., and Ito, H. (2015). Nonalcoholic Hepatic Steatosis Is a Strong Predictor of High-Risk Coronary-Artery Plaques as Determined by Multidetector CT. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131138"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1016\/j.jacc.2018.03.509","article-title":"Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium","volume":"71","author":"Packer","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"984","DOI":"10.3945\/ajcn.117.157115","article-title":"Dynamics of intrapericardial and extrapericardial fat tissues during long-term, dietary-induced, moderate weight loss","volume":"106","author":"Tsaban","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1136\/gutjnl-2017-313884","article-title":"Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases","volume":"66","author":"Adams","year":"2017","journal-title":"Gut"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1136\/gutjnl-2016-311854","article-title":"Non-alcoholic fatty liver disease and progression of coronary artery calcium score: A retrospective cohort study","volume":"66","author":"Sinn","year":"2016","journal-title":"Gut"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.2337\/dc16-0091","article-title":"Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring","volume":"39","author":"Mantovani","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"K\u00e4r\u00e4j\u00e4m\u00e4ki, A.J., P\u00e4tsi, O.-P., Savolainen, M.J., Kes\u00e4niemi, Y.A., Huikuri, H.V., and Ukkola, O. (2015). Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle-Aged Population (OPERA Study). PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142937"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1097\/HJH.0000000000000532","article-title":"Blood pressure is associated with the presence and severity of nonalcoholic fatty liver disease across the spectrum of cardiometabolic risk","volume":"33","author":"Aneni","year":"2015","journal-title":"J. Hypertens."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrendo.2014.29","article-title":"Insulin resistance and hyperglycaemia in cardiovascular disease development","volume":"10","author":"Laakso","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1136\/gutjnl-2018-317666","article-title":"Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: Evidence from the Kangbuk Samsung Health Study","volume":"68","author":"Chang","year":"2018","journal-title":"Gut"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S2213-8587(18)30154-2","article-title":"Non-alcoholic fatty liver disease: Causes, diagnosis, cardiometabolic consequences, and treatment strategies","volume":"7","author":"Stefan","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_137","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_138","first-page":"1024","article-title":"Total Body Weight Loss of \u226510 % Is Associated with Improved Hepatic Fibrosis in Patients with Nonalcoholic Steatohepatitis","volume":"60","author":"Glass","year":"2014","journal-title":"Am. J. Dig. Dis."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1161\/CIRCULATIONAHA.117.030501","article-title":"Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools","volume":"137","author":"Gepner","year":"2018","journal-title":"Circulation"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fmed.2019.00202","article-title":"Cardiovascular Risk in Fatty Liver Disease: The Liver-Heart Axis\u2014Literature Review","volume":"6","author":"Ismaiel","year":"2019","journal-title":"Front. Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1161\/ATVBAHA.119.313286","article-title":"Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid","volume":"40","author":"Mason","year":"2020","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jhep.2013.02.012","article-title":"The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease","volume":"59","author":"Ryan","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.jhep.2011.06.010","article-title":"Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: A systematic review","volume":"56","author":"Thoma","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jhep.2012.02.023","article-title":"Exercise and non-alcoholic fatty liver disease: A systematic review and meta-analysis","volume":"57","author":"Keating","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1001\/jama.2018.14854","article-title":"The Physical Activity Guidelines for Americans","volume":"320","author":"Piercy","year":"2018","journal-title":"JAMA"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.tips.2020.09.001","article-title":"Metformin and Systemic Metabolism","volume":"41","author":"He","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/apt.15331","article-title":"Long-term metformin use may improve clinical outcomes in diabetic patients with non-alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis","volume":"50","author":"Vuppalanchi","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_148","first-page":"136","article-title":"Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Nonalcoholic Steatohepatitis\u2013Related, Child\u2013Pugh A Cirrhosis","volume":"19","author":"Wong","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1007\/s00125-018-4675-2","article-title":"Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: A double-blind randomised placebo-controlled study","volume":"61","author":"Eriksson","year":"2018","journal-title":"Diabetologia"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"298","DOI":"10.2337\/dc19-0641","article-title":"Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial","volume":"43","author":"Kahl","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrendo.2016.135","article-title":"PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD","volume":"13","author":"Gross","year":"2016","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1001\/jamainternmed.2016.9607","article-title":"Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis","volume":"177","author":"Musso","year":"2017","journal-title":"JAMA Intern. Med."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/S0140-6736(05)67528-9","article-title":"Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial","volume":"366","author":"Dormandy","year":"2005","journal-title":"Lancet"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nm.3159","article-title":"PPAR\u03b3 signaling and metabolism: The good, the bad and the future","volume":"19","author":"Ahmadian","year":"2013","journal-title":"Nat. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2147\/HMER.S158053","article-title":"Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: A 1-year randomized control trial","volume":"10","author":"Alam","year":"2018","journal-title":"Hepatic Med. Evid. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2S28","DOI":"10.1016\/S1262-3636(17)30070-8","article-title":"GLP-1 receptor agonists in NAFLD","volume":"43","author":"Petit","year":"2017","journal-title":"Diabetes Metab."},{"key":"ref_157","first-page":"407","article-title":"Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes. The Lira-NAFLD study","volume":"102","author":"Petit","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1016\/S0140-6736(19)32517-6","article-title":"Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial","volume":"394","author":"Harrison","year":"2019","journal-title":"Lancet"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1056\/NEJMoa2028395","article-title":"A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis","volume":"384","author":"Newsome","year":"2021","journal-title":"New Engl. J. Med."},{"key":"ref_160","first-page":"3402","article-title":"Efficacy of Probiotics and Synbiotics in Patients with Nonalcoholic Fatty Liver Disease: A Meta-Analysis","volume":"64","author":"Liu","year":"2019","journal-title":"Am. J. Dig. Dis."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s11892-008-0027-9","article-title":"Genes and nonalcoholic fatty liver disease","volume":"8","author":"Day","year":"2008","journal-title":"Curr. Diabetes Rep."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1111\/apt.12758","article-title":"Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis","volume":"39","author":"Alisi","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Gottlieb, A., and Canbay, A. (2019). Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression. Cells, 8.","DOI":"10.3390\/cells8111358"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"172661","DOI":"10.1016\/j.ejphar.2019.172661","article-title":"Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis","volume":"863","author":"Venetsanaki","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Stofan, M., and Guo, G.L. (2020). Bile Acids and FXR: Novel Targets for Liver Diseases. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00544"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1053\/j.gastro.2020.08.004","article-title":"Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis","volume":"160","author":"Harrison","year":"2021","journal-title":"Gastroenterology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5146\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:06:20Z","timestamp":1760137580000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,5]]},"references-count":166,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095146"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095146","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,5]]}}}