24S-Hydroxycholesterol
Cerebrosterol.svg
Names
IUPAC name
Cholest-5-ene-3,24-diol
Preferred 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

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

Function

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] 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.[9] Blood plasma levels of 24S-HC may be altered after acute brain injuries such as stroke[10] or in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and multiple sclerosis.[11][12]

References

  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. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.