{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:54:38Z","timestamp":1792119278048,"version":"4.4.0"},"reference-count":59,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24118003"],"award-info":[{"award-number":["JP24118003"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K06489"],"award-info":[{"award-number":["JP20K06489"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP17H04044"],"award-info":[{"award-number":["JP17H04044"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Usp21, a member of the ubiquitin protease family, plays a vital role in various biological functions. However, the effects of Usp21 dysfunction remain incompletely understood. In this study, we generated Usp21 knockout (KO) mice. Blood tests showed no impairment of liver function but did reveal elevated levels of total cholesterol (T-CHOL) and free fatty acid (FFA) in Usp21 KO mice compared to wild-type (WT) mice. Next, we performed RNA-sequencing (RNA-seq) to identify genes that Usp21 regulates. The results highlighted several candidate genes based on their biological relevance, and their expression levels were validated by RT-qPCR. The Usp21 KO mice exhibited significant elevations in the expression of the genes Fabp7, Nlrc5, and Ppargc1a, which play an important role in lipid metabolism, compared to WT. These data suggest that Usp21 may play roles in lipid metabolism in association with Fabp7, Nlrc5 and Ppargc1a. To clarify the involvement of USP21 in human hypercholesterolemia, we examined single-nucleotide polymorphisms (SNPs) around USP21 in non-hypercholesterolemic and hypercholesterolemic outpatients. We found that the rs11421 SNP downstream of USP21 was significantly associated with hypercholesterolemia. These data suggest that Usp21 plays a role in mice and human lipid metabolism and that its polymorphism may be a diagnostic marker for human hypercholesterolemia.<\/jats:p>","DOI":"10.3390\/ijms26199727","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"9727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Usp21 Knockout Causes Abnormal Lipid Metabolism in Mouse and Its Polymorphism Correlates with Hypercholesterolemia in Outpatients"],"prefix":"10.3390","volume":"26","author":[{"given":"Sailakshmi","family":"Iyer","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3142-8400","authenticated-orcid":false,"given":"Naoko","family":"Hattori","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"},{"name":"Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Okuda","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0687-2248","authenticated-orcid":false,"given":"Takeya","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3341-8644","authenticated-orcid":false,"given":"Satoshi","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Fukuoka 804-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"},{"name":"Department of Island and Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1146\/annurev.biophys.36.040306.132820","article-title":"Structural mechanisms underlying posttranslational modification by ubiquitin-like proteins","volume":"36","author":"Dye","year":"2007","journal-title":"Annu. 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