{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:22:53Z","timestamp":1773307373858,"version":"3.50.1"},"reference-count":107,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tokushima Bunri University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Although the brain comprises only 2% of total body weight, it contains approximately 23% of the total cholesterol of the body. In the brain, cholesterol plays a critical role as a structural component of cell membranes and myelin sheaths. However, the blood\u2013brain barrier restricts cholesterol influx from the systemic circulation into the brain. As a result, the brain synthesizes cholesterol de novo and regulates its metabolism independently. Desmosterol, a cholesterol precursor produced during cholesterol biosynthesis, and cholesterol metabolites, 24S-hydroxycholesterol and chenodeoxycholic acid, are sterols with structurally retained side chains. These side-chain-retaining sterols have traditionally been regarded as intermediates in the cholesterol synthesis process or as metabolites for cholesterol excretion, but accumulating evidence indicates that they also function as physiologically active signaling molecules that influence brain function via nuclear receptors, such as liver X receptors, and membrane receptors, such as NMDA receptors. Through nuclear receptors, these side-chain-retaining sterols regulate the transcription of genes involved in lipid transport, inflammation control, and amyloid clearance, while their membrane receptor action enables rapid synaptic effects. These side-chain-retaining sterols mediate metabolic crosstalk between neurons and glial cells and contribute to maintaining cholesterol balance in the developing brain. Furthermore, these side-chain-retaining sterols have been shown to affect amyloid-\u03b2 clearance, \u03b1-synuclein aggregation, neuroinflammation, mitochondrial function, and remyelination. Dysregulation of these side-chain-retaining sterols is associated with neurodegenerative diseases such as Alzheimer\u2019s disease and Parkinson\u2019s disease. Overall, side-chain-retaining sterols are important regulators of brain physiology. This review focuses on the current knowledge regarding the physiological functions of side-chain-retaining sterols in the brain and their roles in neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/metabo16030189","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T14:43:18Z","timestamp":1773240198000},"page":"189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiological Functions of Side-Chain-Retaining Sterols in the Brain and Their Roles in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-483X","authenticated-orcid":false,"given":"Yoshimitsu","family":"Kiriyama","sequence":"first","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Hamanochou 8-53, Takamatsu 760-8542, Kagawa, Japan"},{"name":"Institute of Neuroscience, Tokushima Bunri University, Hamanochou 8-53, Takamatsu 760-8542, Kagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Nakatsuma","sequence":"additional","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Hamanochou 8-53, Takamatsu 760-8542, Kagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Tokumaru","sequence":"additional","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Hamanochou 8-53, Takamatsu 760-8542, Kagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1838-0649","authenticated-orcid":false,"given":"Hisayo","family":"Sadamoto","sequence":"additional","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Hamanochou 8-53, Takamatsu 760-8542, Kagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2352-8716","authenticated-orcid":false,"given":"Hiromi","family":"Nochi","sequence":"additional","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Hamanochou 8-53, Takamatsu 760-8542, Kagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"135455","DOI":"10.1016\/j.neulet.2020.135455","article-title":"Mini review: Lipids in Peripheral Nerve Disorders","volume":"740","author":"Hornemann","year":"2021","journal-title":"Neurosci. 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