{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:30:41Z","timestamp":1791419441685,"version":"4.3.3"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,14]],"date-time":"2020-11-14T00:00:00Z","timestamp":1605312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HO4460\/3-1"],"award-info":[{"award-number":["HO4460\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009401","name":"Medizinischen Fakult\u00e4t, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen","doi-asserted-by":"publisher","award":["F\u00f6FoLe #905"],"award-info":[{"award-number":["F\u00f6FoLe #905"]}],"id":[{"id":"10.13039\/501100009401","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life \u201cAmerican lifestyle-induced obesity syndrome\u201d (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r\u2212\/\u2212- but not Il-1r\u2212\/\u2212 mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.<\/jats:p>","DOI":"10.3390\/ijms21228602","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T21:48:52Z","timestamp":1605563332000},"page":"8602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["IL-18 But Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-6317","authenticated-orcid":false,"given":"Simon","family":"Hohenester","sequence":"first","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Kanitz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine, LMU Munich, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Schiergens","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Einer","sequence":"additional","affiliation":[{"name":"Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Nagel","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Wimmer","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian P.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander L.","family":"Gerbes","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico N.","family":"De Toni","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1349-0160","authenticated-orcid":false,"given":"Christian","family":"Bauer","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Endocrinology, Infectiology and Metabolism, University Hospital Giessen and Marburg, Campus Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesca","family":"Holdt","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Mayr","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine, LMU Munich, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Rust","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Hospital Barmherzige Br\u00fcder, 80639 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Schnurr","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, University Hospital, LMU Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4047-1566","authenticated-orcid":false,"given":"Hans","family":"Zischka","sequence":"additional","affiliation":[{"name":"Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany"},{"name":"Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Geier","sequence":"additional","affiliation":[{"name":"Division of Hepatology, University Hospital W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Denk","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany"},{"name":"Transplantation Center Munich, University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,14]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1136\/gutjnl-2019-318813","article-title":"Epidemiology of chronic liver diseases in the USA in the past three decades","volume":"69","author":"Younossi","year":"2019","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41575-019-0144-8","article-title":"Past, present and future perspectives in nonalcoholic fatty liver disease","volume":"16","author":"Sanyal","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"EASL, EASD, and EASO (2016). 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","first-page":"G329","article-title":"Lifestyle intervention for morbid obesity: Effects on liver steatosis, inflammation, and fibrosis","volume":"315","author":"Hohenester","year":"2018","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_7","first-page":"746","article-title":"ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis","volume":"67","author":"Mahli","year":"2018","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1007\/s00204-016-1892-7","article-title":"Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD)","volume":"91","author":"Alwahsh","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_9","first-page":"1376","article-title":"Aerobic capacity and exercise performance in nonalcoholic fatty liver disease","volume":"59","author":"Austin","year":"2019","journal-title":"J. Sports Med. Phys. Fit."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Alwahsh, S.M., Xu, M., Schultze, F.C., Wilting, J., Mihm, S., Raddatz, D., and Ramadori, G. (2014). Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104220"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6668","DOI":"10.1038\/s41598-019-43228-0","article-title":"Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine","volume":"9","author":"Brandt","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2017.08.015","article-title":"Mitochondrial adaptation in steatotic mice","volume":"40","author":"Einer","year":"2018","journal-title":"Mitochondrion"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.dib.2017.09.019","article-title":"Data on chow, liver tissue and mitochondrial fatty acid compositions as well as mitochondrial proteome changes after feeding mice a western diet for 6\u201324 weeks","volume":"15","author":"Einer","year":"2017","journal-title":"Data Brief"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.jcmgh.2018.12.005","article-title":"A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats","volume":"7","author":"Einer","year":"2019","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1111\/liv.12685","article-title":"Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis","volume":"35","author":"Yamada","year":"2014","journal-title":"Liver Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/ni.2022","article-title":"Fatty acid\u2013induced NLRP3-ASC inflammasome activation interferes with insulin signaling","volume":"12","author":"Wen","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev-cellbio-101011-155745","article-title":"Inflammasomes and Their Roles in Health and Disease","volume":"28","author":"Lamkanfi","year":"2012","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1053\/j.gastro.2012.09.008","article-title":"Sterile Inflammation in the Liver","volume":"143","author":"Kubes","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.cell.2004.05.004","article-title":"Inflammatory Caspases: Linking an intracellular innate immune system to autoinflammatory diseases","volume":"117","author":"Martinon","year":"2004","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/hep.24341","article-title":"Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells","volume":"54","author":"Csak","year":"2011","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Simoes, I.C.M., Janikiewicz, J., Bauer, J., Karkuci\u0144ska-Wi\u0119ckowska, A., Kalinowski, P., Dobrzy\u0144, A., Wolski, A., Pronicki, M., Zieniewicz, K., and Dobrzyn, P. (2019). Fat and Sugar\u2014A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease. Nutrients, 11.","DOI":"10.3390\/nu11122871"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"G987","DOI":"10.1152\/ajpgi.90272.2008","article-title":"Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent","volume":"295","author":"Tetri","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1002\/hep.26937","article-title":"The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease","volume":"59","author":"Gadd","year":"2014","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.2337\/db10-0224","article-title":"Adipose Tissue Dysfunction Signals Progression of Hepatic Steatosis Towards Nonalcoholic Steatohepatitis in C57Bl\/6 Mice","volume":"59","author":"Duval","year":"2010","journal-title":"Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.cbi.2019.01.004","article-title":"Chronic intake of moderate fat-enriched diet induces fatty liver and low-grade inflammation without obesity in rabbits","volume":"300","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_26","first-page":"3870454","article-title":"Predictive Role of Interleukin-18 in Liver Steatosis in Obese Children","volume":"2018","author":"Wojtkowska","year":"2018","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"McKie, E.A., Reid, J.L., Mistry, P.C., DeWall, S.L., Abberley, L., Ambery, P.D., and Gil-Extremera, B. (2016). A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150018"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10809","article-title":"Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity","volume":"482","author":"Elinav","year":"2012","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"401","DOI":"10.4254\/wjh.v8.i8.401","article-title":"Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4(-\/-) mouse model","volume":"8","author":"Reiter","year":"2016","journal-title":"World J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1053\/j.gastro.2010.03.052","article-title":"Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice","volume":"139","author":"Miura","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.jhep.2011.01.048","article-title":"Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice","volume":"55","author":"Kamari","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1007\/s12272-016-0827-4","article-title":"Mitochondria and the NLRP3 inflammasome: Physiological and pathological relevance","volume":"39","author":"Yu","year":"2016","journal-title":"Arch. Pharmacal. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1002\/hep.25889","article-title":"Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients","volume":"56","author":"Bedossa","year":"2012","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liang, W., Menke, A.L., Driessen, A., Koek, G.H., Lindeman, J.H., Stoop, R., Havekes, L.M., Kleemann, R., and Hoek, A.M.V.D. (2014). Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115922"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0009-8981(80)90192-8","article-title":"Modified assay for determination of hydroxyproline in a tissue hydrolyzate","volume":"104","author":"Edwards","year":"1980","journal-title":"Clin. Chim. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1023\/A:1026392429112","article-title":"Charitable State-Controlled Foundation Human Tissue and Cell Research: Ethic and Legal Aspects in the Supply of Surgically Removed Human Tissue for Research in the Academic and Commercial Sector in Germany","volume":"4","author":"Thasler","year":"2003","journal-title":"Cell Tissue Bank."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/978-1-4939-2550-6_7","article-title":"A Protocol for the Parallel Isolation of Intact Mitochondria from Rat Liver, Kidney, Heart, and Brain","volume":"1295","author":"Schulz","year":"2015","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8602\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:33:31Z","timestamp":1760178811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,14]]},"references-count":39,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228602"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228602","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,14]]}}}