24S-Hydroxycholesterol

24S-Hydroxycholesterol
Names
IUPAC name
(24S)-Cholest-5-ene-3β,24-diol
Systematic IUPAC name
(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,5S)-5-Hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[a]phenanthren-7-ol
Other names
cerebrosterol
Identifiers
3D model (JSmol)
3218472
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C27H46O2/c1-17(2)25(29)11-6-18(3)22-9-10-23-21-8-7-19-16-20(28)12-14-26(19,4)24(21)13-15-27(22,23)5/h7,17-18,20-25,28-29H,6,8-16H2,1-5H3/t18-,20+,21+,22-,23+,24+,25+,26+,27-/m1/s1
    Key: IOWMKBFJCNLRTC-XWXSNNQWSA-N
  • C[C@H](CC[C@@H](C(C)C)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC=C4[C@@]3(CC[C@@H](C4)O)C)C
Properties
C27H46O2
Molar mass 402.663 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

24S-Hydroxycholesterol (24S-HC), also known as cholest-5-ene-3,24-diol or cerebrosterol, is an endogenous oxysterol produced by neurons in the brain to maintain cholesterol homeostasis.[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]

Structure

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

Production of 24S-hydroxycholesterol from cholesterol, as catalyzed by CYP46A1.

Function

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24S-HC binds to apolipoproteins such as apoE, apoJ, and apoA1 to form HDL-like complexes[5] 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.[1][6] 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.[7]

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.[5] 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.[8]

24S-HC may participate in several aspects of brain development and function, such as axon and dendrite growth or synaptogenesis,[4] as well as acting as a positive allosteric modulator of NMDA receptors.[9] 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.[10] Blood plasma levels of 24S-HC may be altered after acute brain injuries such as stroke[11] or in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and multiple sclerosis.[12][13]

References

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  1. ^ a b 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.
  2. ^ Ercoli A, Di Frisco S, De Ruggieri P (1953). "Isolation, constitution and biological significance of cerebrosterol, a companion of cholesterol in the horse brain". Boll Soc Ital Biol Sper. 29 (4): 494–7. PMID 13105923.
  3. ^ Di Frisco S, De Ruggieri P, Ercoli A (1953). "Isolation of cerebrosterol from human brain". Boll Soc Ital Biol Sper. 29 (7): 1351–2. PMID 13140512.
  4. ^ a b 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.
  5. ^ a b 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.
  6. ^ Björkhem I (2007). "Rediscovery of cerebrosterol". Lipids. 42 (1): 5–14. doi:10.1007/s11745-006-1003-2. PMID 17393206. S2CID 4005673.
  7. ^ 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.
  8. ^ 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.
  9. ^ Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, Crawford DC, Linsenbardt AJ, Shu HJ, Izumi Y, Mennerick SJ, Zorumski CF (October 2013). "The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors". The Journal of Neuroscience. 33 (44): 17290–300. doi:10.1523/JNEUROSCI.2619-13.2013. PMC 3812502. PMID 24174662.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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. PMID 23041502.
  13. ^ 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. PMC 4304132. PMID 25539717.
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