{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:51:48Z","timestamp":1790175108143,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,13]],"date-time":"2019-04-13T00:00:00Z","timestamp":1555113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/C515771\/2"],"award-info":[{"award-number":["BB\/C515771\/2"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/I001735\/1"],"award-info":[{"award-number":["BB\/I001735\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/N015932\/1"],"award-info":[{"award-number":["BB\/N015932\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L001942\/1"],"award-info":[{"award-number":["BB\/L001942\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT73429"],"award-info":[{"award-number":["WT73429"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7\u03b1-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-\/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography\u2013mass spectrometry (LC\u2013MS) and multistage fragmentation (MSn), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-\/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3\u03b2-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-\/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-\/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered.<\/jats:p>","DOI":"10.3390\/biom9040149","type":"journal-article","created":{"date-parts":[[2019,4,15]],"date-time":"2019-04-15T11:15:58Z","timestamp":1555326958000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Mining for Oxysterols in Cyp7b1\u2212\/\u2212 Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5"],"prefix":"10.3390","volume":"9","author":[{"given":"Anna","family":"Meljon","sequence":"first","affiliation":[{"name":"Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK"},{"name":"Institute for Global Food Security, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Crick","sequence":"additional","affiliation":[{"name":"Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9971-1950","authenticated-orcid":false,"given":"Eylan","family":"Yutuc","sequence":"additional","affiliation":[{"name":"Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce L.","family":"Yau","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, BHF Centre for Cardiovascular Science, The Queen\u2019s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Seckl","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, BHF Centre for Cardiovascular Science, The Queen\u2019s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1986-0943","authenticated-orcid":false,"given":"Spyridon","family":"Theofilopoulos","sequence":"additional","affiliation":[{"name":"Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK"},{"name":"Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest","family":"Arenas","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqin","family":"Wang","sequence":"additional","affiliation":[{"name":"Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-6616","authenticated-orcid":false,"given":"William J.","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"29739","DOI":"10.1074\/jbc.270.50.29739","article-title":"A novel cytochrome P450 expressed primarily in brain","volume":"270","author":"Stapleton","year":"1995","journal-title":"J. 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