{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:55:54Z","timestamp":1791050154838,"version":"4.1.0"},"reference-count":28,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["21H03376"],"award-info":[{"award-number":["21H03376"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["24KF0066"],"award-info":[{"award-number":["24KF0066"]}]},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cooperative Research Project Program of the Institute for Protein Research at Osaka University","award":["CR-25-03"],"award-info":[{"award-number":["CR-25-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum (ER) stress, and steatosis, contributing to MASLD progression. Although vitamin E is clinically used for its antioxidant and anti-inflammatory properties, it remains unclear whether its therapeutic effects involve modulation of DAMP-associated signaling. To address this gap, we used transgenic zebrafish expressing a liver-specific G-protein-coupled receptor activation-based adenosine sensor (GRABAdo). We found that a high-cholesterol diet markedly increased hepatic extracellular Ado levels, combined with inflammatory and ER stress-associated gene expression. Vitamin E significantly reduced extracellular Ado levels and hepatic lipid accumulation. Based on RNA sequencing results, vitamin E restored the expression of genes encoding calcium-handling proteins, including atp2a1 and atp1b1b. These genes encode components of the sarco\/ER Ca2+-ATPase (SERCA) machinery, which is essential for maintaining ER Ca2+ homeostasis and preventing stress-induced hepatic injury. CDN1163-mediated SERCA activation phenocopied the protective effect of vitamin E, supporting a Ca2+-dependent mechanism. Together, these findings highlight extracellular Ado signaling and impaired SERCA-mediated Ca2+ regulation as early drivers of MASLD and demonstrate that vitamin E ameliorates steatosis by targeting both pathways.<\/jats:p>","DOI":"10.3390\/ijms27020614","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:02:51Z","timestamp":1767794571000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0634-3568","authenticated-orcid":false,"given":"Mengting","family":"Shan","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-0020","authenticated-orcid":false,"given":"Magdeline E. Carrasco","family":"Apolinario","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6343-2618","authenticated-orcid":false,"given":"Tomoko","family":"Tokumaru","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4395-3787","authenticated-orcid":false,"given":"Kenshiro","family":"Shikano","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phurpa","family":"Phurpa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3982-0431","authenticated-orcid":false,"given":"Ami","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Teranishi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichiro","family":"Kume","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8100-0330","authenticated-orcid":false,"given":"Nobuyuki","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Kurokawa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takatoshi","family":"Hikida","sequence":"additional","affiliation":[{"name":"Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3317-6366","authenticated-orcid":false,"given":"Toshikatsu","family":"Hanada","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-1287","authenticated-orcid":false,"given":"Reiko","family":"Hanada","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1097\/HEP.0000000000000520","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S2468-1253(22)00165-0","article-title":"The prevalence and incidence of NAFLD worldwide: A systematic review and meta-analysis","volume":"7","author":"Riazi","year":"2022","journal-title":"Lancet Gastroenterol. 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