{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:21:43Z","timestamp":1793726503854,"version":"4.6.1"},"reference-count":100,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":53,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology in Japan","award":["24K19130"],"award-info":[{"award-number":["24K19130"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP22gm1410014"],"award-info":[{"award-number":["JP22gm1410014"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004205","name":"Osaka Kidney Foundation","doi-asserted-by":"crossref","award":["OKF23-0004"],"award-info":[{"award-number":["OKF23-0004"]}],"id":[{"id":"10.13039\/501100004205","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006680","name":"Takeda Medical Research Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100006680","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007263","name":"Astellas Foundation for Research on Metabolic Disorders","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100007263","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008734","name":"Mitsui Sumitomo Insurance Welfare Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100008734","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Telethon Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Research Council","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,10]]},"abstract":"<jats:p>\n                    With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy\/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific\n                    <jats:italic>Tfeb<\/jats:italic>\n                    -deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria\u2013lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.184451","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T12:00:16Z","timestamp":1734609616000},"source":"Crossref","is-referenced-by-count":6,"title":["Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4\u2013related amyloidosis"],"prefix":"10.1172","volume":"10","author":[{"given":"Jun","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitsugu","family":"Takabatake","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6049-7616","authenticated-orcid":true,"given":"Tomoko","family":"Namba-Hamano","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5043-3435","authenticated-orcid":true,"given":"Satoshi","family":"Minami","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-9350","authenticated-orcid":true,"given":"Hiroaki","family":"Yonishi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihomi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8378-6130","authenticated-orcid":true,"given":"Isao","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Yamamuro","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuya","family":"Edahiro","sequence":"additional","affiliation":[{"name":"Department of Statistical Genetics and"},{"name":"Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan."},{"name":"Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Takashima","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Takasawa","sequence":"additional","affiliation":[{"name":"Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinori","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Statistical Genetics and"},{"name":"Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan."},{"name":"Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe) and"},{"name":"Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan."},{"name":"Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamotsu","family":"Yoshimori","sequence":"additional","affiliation":[{"name":"Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Naples, Italy."},{"name":"Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, Naples, Italy."},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children\u2019s Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Isaka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kisu.2021.11.003"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30045-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32203-7"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024816"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-021-00098-4"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01251-0"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.08.069"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2772"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.05.002"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nature06639"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010070705"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.11.001"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.171"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016070731"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1341464"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1159376"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018100983"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0397"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2259282"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.0000000000000414"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174447"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1204592"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.101985"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3267"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.08.005"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28874-9"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201501002"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.146365"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.11.003"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10944"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110444"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306454120"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-020-0265-4"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.162498"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-00583-9"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature11861"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002790"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1712107"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.44.28142"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17047"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-003-0834-y"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2008.72"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.657"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2023.03.002"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00483-7"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1172\/JCI140903"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-021-03073-x"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.6.3.277"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.00519.x"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)47513-8"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.301948"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-017-0473-y"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2718"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113291"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3762"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.062"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.06.003"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.01.029"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00110.2008"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114253"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2018.10.004"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2018.00082"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418560112"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.171961"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.05.027"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1002\/path.5100"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/srep16474"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.022"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101388"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2015.0052"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1021\/pr100520x"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M600178-JLR200"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1002\/path.5770"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.11.021"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.04.003"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12380"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1159\/000350158"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2023.2169603"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.2147\/IJNRD.S101808"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00098.2014"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114142"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1002\/path.6029"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.09.006"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202207097"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01502-8"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022111241"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00615-8"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15750"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giaa151"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.03.003"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0844-5"},{"issue":"3","key":"B95","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1782034"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013090986"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2020.100245"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700518"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1080"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/184451\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T20:27:52Z","timestamp":1779136072000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/184451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,19]]},"references-count":100,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2,10]]},"published-print":{"date-parts":[[2025,2,10]]}},"alternative-id":["10.1172\/jci.insight.184451"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.184451","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,19]]},"article-number":"e184451"}}