{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:28:22Z","timestamp":1792024102126,"version":"4.4.0"},"reference-count":68,"publisher":"American Society for Clinical Investigation","issue":"21","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIAAA intramural program","award":["AA000369"],"award-info":[{"award-number":["AA000369"]}]},{"name":"NIAAA intramural program","award":["AA000368"],"award-info":[{"award-number":["AA000368"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,3]]},"abstract":"<jats:p>\n                    Both adipocytes and hepatocytes have the capacity to store fat, but the factor(s) that determine fat distribution between these cell types remain unknown. In mice fed a high-fat diet, fat initially accumulates predominantly in adipocytes, while hepatic fat accumulation mainly emerges after the onset of epididymal adipocyte death that results in elevated free fatty acids to promote lipid accumulation in hepatocytes. However, it remains unclear whether other signals after adipocyte death are required to direct and\/or promote hepatocytes to store fat and subsequently trigger metabolic dysfunction\u2013associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease). Using genetically modified mouse models combined with bulk and single-cell RNA-Seq analysis, we demonstrated that visceral adipocyte death induced an accumulation of S100A8\n                    <jats:sup>+<\/jats:sup>\n                    macrophages in the liver, which was partially induced by fatty acids and apoptotic adipocyte\u2013derived extracellular vesicles. Macrophage-specific deletion of the\n                    <jats:italic>S100a8<\/jats:italic>\n                    gene reduced hepatic fat accumulation and MASLD severity in mice. Mechanistically, S100A8\n                    <jats:sup>+<\/jats:sup>\n                    macrophages suppressed cellular communication network factor 3 (CCN3), a negative regulator of CD36, thereby enhancing CD36 expression in hepatocytes. In conclusion, adipocyte death promotes hepatic infiltration of S100A8\n                    <jats:sup>+<\/jats:sup>\n                    macrophages, which drive hepatocyte lipid storage and subsequently promote MASLD progression through CD36 upregulation, partially mediated by CCN3 suppression.\n                  <\/jats:p>","DOI":"10.1172\/jci190635","type":"journal-article","created":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T19:01:03Z","timestamp":1762110063000},"source":"Crossref","is-referenced-by-count":12,"title":["Adipocyte death promotes hepatic infiltration of S100A8+ macrophages and steatotic liver disease progression in mice"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9312-0164","authenticated-orcid":true,"given":"Yukun","family":"Guan","sequence":"first","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye Eun","family":"Cho","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-2950","authenticated-orcid":true,"given":"Xiaogang","family":"Xiang","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Yao","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dechun","family":"Feng","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seonghwan","family":"Hwang","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."},{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1503519"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.031"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/egastro-2023-100020"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.01.052"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1479"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1055\/a-2186-3557"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M500294-JLR200"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/21623945.2021.1982164"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2152\/jmi.64.193"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45887"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.074252"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38388"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.170"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-0194"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-255992"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01298"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nm1638"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/850246"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/828354"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92450"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.08.002"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.4.2209"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/ar1939"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgn188"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401085"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-16754-7"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/cells11223579"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-015-0281-y"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30171"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193060"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080241"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-010-0085-z"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094912"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.87"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-023-00765-8"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-017-0432-4"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R700014-JLR200"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2337\/db07-0767"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2011.01488.x"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2405746121"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.11.013"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk1866"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M028035"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.08.001"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3719-0"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae028"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.11.037"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04629-z"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.054"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.07.028"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1631-3"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1172\/JCI166954"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.01.020"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-021-00659-7"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-022-01020-0"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0207228"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30525"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.07.015"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1187741"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.2337\/db15-0617"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.69"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-013-0922-5"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2015.12.012"},{"issue":"6","key":"B65","doi-asserted-by":"crossref","DOI":"10.1097\/HC9.0000000000000716","article-title":"VLDL lipidomics reveals hepatocellular lipidome changes in metabolic dysfunction-associated steatotic liver disease","volume":"9","author":"Guardamino Ojeda","year":"2025","journal-title":"Hepatol Commun"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.11.013"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-59970-9"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/190635\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:58:47Z","timestamp":1779213527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/190635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":68,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,8,28]]},"published-print":{"date-parts":[[2025,11,3]]}},"alternative-id":["10.1172\/JCI190635"],"URL":"https:\/\/doi.org\/10.1172\/jci190635","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,3]]},"article-number":"e190635"}}