Primary human astrocytes produce 24(S),25-epoxycholesterol with implications for brain cholesterol homeostasis

Jenny Wong, Carmel M. Quinn, Gilles Guillemin, Andrew J. Brown*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Cholesterol is an essential component of the CNS and its metabolism in the brain has been implicated in various neurodegenerative diseases. The oxysterol produced from cholesterol, 24(S)-hydroxycholesterol, is known to be an important regulator of brain cholesterol homeostasis. In this study, we focussed on another oxysterol, 24(S),25-epoxycholesterol (24,25EC), which has not been studied before in a neurological context. 24,25EC is unique in that it is synthesized in a shunt in the mevalonate pathway, parallel to cholesterol and utilizing the same enzymes. Considering that all the cholesterol present in the brain is derived from de novo synthesis, we investigated whether or not primary human neurons and astrocytes can produce 24,25EC. We found that astrocytes produced more 24,25EC than neurons under basal conditions, but both cell types had the capacity to synthesize this oxysterol when the enzyme 2,3-oxidosqualene cyclase was partially inhibited. Furthermore, both added 24,25EC and stimulated cellular production of 24,25EC (by partial inhibition of 2,3-oxidosqualene cyclase) modulated expression of key cholesterol-homeostatic genes regulated by the liver X receptor and the sterol regulatory element-binding protein-2. Moreover, we found that 24,25EC synthesized in astrocytes can be taken up by neurons and exert downstream effects on gene regulation. In summary, we have identified 24,25EC as a novel neurosterol which plays a likely role in brain cholesterol homeostasis.

Original languageEnglish
Pages (from-to)1764-1773
Number of pages10
JournalJournal of Neurochemistry
Volume103
Issue number5
DOIs
Publication statusPublished - Dec 2007
Externally publishedYes

Keywords

  • ATP-binding cassette transporter A1
  • ATP-binding cassette transporter G1
  • Central nervous system
  • Liver X receptor
  • Oxysterol
  • Sterol regulatory element-binding protein-2

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