{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:36:44Z","timestamp":1791578204852,"version":"4.3.4"},"reference-count":69,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R42DK135208"],"award-info":[{"award-number":["R42DK135208"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Although the progression of non\u2010alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT\u2010100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH\/hepatic fibrosis. ALT\u2010100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage\u2010associated molecular pattern protein (DAMP) and Toll\u2010like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin\/high\u2010fat diet\u2014STZ\/HFD, 12\u2009weeks). Human NAFLD subjects (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a05) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL\u20106, Ang\u20102, and IL\u20101RA compared to healthy controls, with IL\u20106 and Ang\u20102 levels significantly increased in NASH non\u2010survivors. Untreated STZ\/HFD\u2010exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL\u20106, and TNF\u03b1), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT\u2010neutralizing ALT\u2010100 mAb (0.4\u00a0mg\/kg\/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression\/severity. Thus, activation of the eNAMPT\/TLR4 inflammatory pathway contributes to NAFLD severity and NASH\/hepatic fibrosis. ALT\u2010100 is potentially an effective therapeutic approach to address this unmet NAFLD need.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201972rr","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T13:05:52Z","timestamp":1676984752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Involvement of\n                    <scp>eNAMPT<\/scp>\n                    \/\n                    <scp>TLR4<\/scp>\n                    inflammatory signaling in progression of non\u2010alcoholic fatty liver disease, steatohepatitis, and fibrosis"],"prefix":"10.1096","volume":"37","author":[{"given":"Belinda L.","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pathology, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-8294","authenticated-orcid":false,"given":"Xiaoguang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie L.","family":"Kempf","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin H.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy G.","family":"Casanova","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Camp","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Reyes\u00a0Hernon","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Fallon","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bime","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Radiology and the Translational Imaging Center Houston Methodist Hospital and the Houston Methodist Research Institute  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Travelli","sequence":"additional","affiliation":[{"name":"Department of Drug Science University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna D.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6934-0420","authenticated-orcid":false,"given":"Joe\u00a0G.\u00a0N.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1159\/000282080"},{"key":"e_1_2_11_3_1","first-page":"273","article-title":"The natural history and risk factors for progression of non\u2010alcoholic fatty liver disease and steatohepatitis","volume":"9","author":"Miele L","year":"2005","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612826666200303114934"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.109"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/imj.14709"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0145-7"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2012.10.001"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1503519"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gastrohep.2017.12.003"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2021.07.013"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep13135"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2021-0357OC"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.916159"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017-0155OC"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-04444-9"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200712-1822OC"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02536-2020"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0117OC"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200404-563OC"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2021.06.002"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2019-0164OC"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.024557"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/20458940211059712"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtauto.2022.100181"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep06107"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-589069"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.103059"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph14121322"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00358"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.117"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12055-2"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.78"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.01911.x"},{"key":"e_1_2_11_36_1","article-title":"Hepatoprotective effects of Aureobasidium pullulans derived beta 1,3\u20101,6 biological response modifier glucans in a STAM\u2010 animal model of non\u2010alcoholic steatohepatitis","author":"Nobunao Ikewaki GK","year":"2021","journal-title":"BioRixv"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.3465"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-019-2697-x"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12871-022-01718-1"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2020.12.008"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24376"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0259OC"},{"key":"e_1_2_11_45_1","first-page":"4181","article-title":"Endogenous Nampt upregulation is associated with diabetic nephropathy inflammatory\u2010fibrosis through the NF\u2010kappaB p65 and Sirt1 pathway; NMN alleviates diabetic nephropathy inflammatory\u2010fibrosis by inhibiting endogenous Nampt","volume":"14","author":"Chen Y","year":"2017","journal-title":"Exp Ther Med"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.03.024"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00468.2012"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2015.07.002"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.01.006"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-010-9219-x"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.09.008"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22136921"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101669"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-62190-w"},{"key":"e_1_2_11_55_1","first-page":"2895","article-title":"Role of Nampt overexpression in a rat model of Hashimoto's thyroiditis and its mechanism of action","volume":"19","author":"Tang JZ","year":"2020","journal-title":"Exp Ther Med"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-010-2042-z"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.1201"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-4076-3"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-05029-y"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.15465"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-017-1415-1"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0009-6"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10809"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1080\/23723556.2015.1052180"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-009-1125-3"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212523"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2148"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-017-0464-z"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf8271"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe8939"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202201972RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202201972RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202201972RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T22:45:40Z","timestamp":1761691540000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202201972RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,21]]},"references-count":69,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,3]]}},"alternative-id":["10.1096\/fj.202201972RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202201972rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,21]]},"assertion":[{"value":"2022-11-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e22825"}}