• 24S-Hydroxycholesterol (24S-HC), also known as cholest-5-ene-3,24-diol or cerebrosterol, is an endogenousoxysterol produced by neurons in the brain to maintain cholesterolhomeostasis.
  • ^[1] 
• It was discovered in 1953 by Alberto Ercoli, S. Di Frisco, and Pietro de Ruggieri, who first isolated the molecule in the horse brain
  • ^[2]
• and then demonstrated its presence in the human brain.
  • ^[3]

• 24S-HC is produced by a hydroxy group substitution at carbon number 24 in cholesterol, catalyzed by the enzyme cholesterol 24-hydroxylase (CYP46A1).
  • ^[4]

Function

• 24S-HC binds to apolipoproteins such as apoE, apoJ, and apoA1 to form HDL-like complexes
  • ^{Wang Y, Kumar N, Crumbley C, Griffin PR, Burris TP (2010). “A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol)”. Biochim Biophys Acta. 1801 (8): 917–23. doi:10.1016/j.bbalip.2010.02.012. PMC 2886165. PMID 20211758.}
•  which can cross the blood-brain barrier more easily than free cholesterol. Thus, 24S-HC production serves as one of several counterbalancing mechanisms for cholesterol synthesis in the brain.
  • ^{Mahley RW (2016). “Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism”. Arterioscler Thromb Vasc Biol. 36 (7): 1305–15. doi:10.1161/ATVBAHA.116.307023. PMC 4942259. PMID 27174096.}
  • ^{Björkhem I (2007). “Rediscovery of cerebrosterol”. Lipids. 42 (1): 5–14. doi:10.1007/s11745-006-1003-2. PMID 17393206. S2CID 4005673} 
• After entering general blood circulation and traveling to the liver, 24S-HC can be sulfated, glucuronidated, or converted into bile acids, which can ultimately be excreted.
  • ^{Lütjohann D (2006). “Cholesterol metabolism in the brain: importance of 24S-hydroxylation”. Acta Neurol Scand Suppl. 185: 33–42. doi:10.1111/j.1600-0404.2006.00683.x. PMID 16866909. S2CID 44809894.}

• 24S-HC is an agonist of liver X receptors, a class of nuclear receptors that sense oxysterols. In the brain, liver X receptor beta is the primary LXR type which interacts with 24S-HC.
  • ^{Wang Y, Kumar N, Crumbley C, Griffin PR, Burris TP (2010). “A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol)”. Biochim Biophys Acta. 1801 (8): 917–23. doi:10.1016/j.bbalip.2010.02.012. PMC 2886165. PMID 20211758.} 
• 24S-HC levels sensed by LXRs can regulate the expression of SREBP mRNA and protein, which in turn regulate cholesterol synthesis and fatty acid synthesis.
  • ^{Cartagena CM, Burns MP, Rebeck GW (2010). “24S-hydroxycholesterol effects on lipid metabolism genes are modeled in traumatic brain injury”. Brain Res. 1319: 1–12. doi:10.1016/j.brainres.2009.12.080. PMC 2826556. PMID 20053345}

• 24S-HC may participate in several aspects of brain development and function, such as axon and dendrite growth or synaptogenesis.
  • ^{Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW (2003). “Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover”. J Biol Chem. 278 (25): 22980–8. doi:10.1074/jbc.M303415200. PMID 12686551} 
• Regulation of 24S-HC metabolism in neurons may play a role in their health and function, as well as their response to injury or disease.
  • ^{Sun MY, Linsenbardt AJ, Emnett CM, Eisenman LN, Izumi Y, Zorumski CF, Mennerick S (2016). “24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival”. Neuroscientist. 22 (2): 132–44. doi:10.1177/1073858414568122. PMC 4821654. PMID 25628343} 
• Blood plasma levels of 24S-HC may be altered after acute brain injuries such as stroke
  • ^{Sun MY, Taylor A, Zorumski CF, Mennerick S (2017). “24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation”. PLOS ONE. 12 (3): e0174416. Bibcode:2017PLoSO..1274416S. doi:10.1371/journal.pone.0174416. PMC 5367825. PMID 28346482}
• or in neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and multiple sclerosis.
  •  ^{Leoni V, Caccia C (2013). “24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases”. Biochimie. 95 (3): 595–612. doi:10.1016/j.biochi.2012.09.025. PMID23041502}
  •  ^{Bandaru VV, Haughey NJ (2014). “Quantitative detection of free 24S-hydroxycholesterol, and 27-hydroxycholesterol from human serum”. BMC Neurosci. 15: 137. doi:10.1186/s12868-014-0137-z. PMC4304132. PMID25539717}