Oxysterols in the brain of the cholesterol 24-hydroxylase knockout mouse

https://doi.org/10.1016/j.bbrc.2014.01.153Get rights and content
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Highlights

  • 24S-Hydroxycholesterol is almost absent from brain of the Cyp46a1−/− mouse.

  • It is not quantitatively replaced by another oxysterol.

  • Minor amounts of 22R-, 24R-, 25- and (25R),26-hydroxycholesterols are present.

  • Cholesterol biosynthesis is reduced in brain of the Cyp46a1−/− mouse.

  • 24S,25-Epoxycholesterol synthesis is reduced in brain of the Cyp46a1−/− mouse.

Abstract

Oxysterols are oxidised forms of cholesterol or its precursors. In this study we utilised the cholesterol 24-hydroxylase knockout mouse (Cyp46a1−/−) to study the sterol and oxysterol content of brain. Despite a great reduction in the abundance of 24S-hydroxycholesterol, the dominant metabolite of cholesterol in wild type brain, no other cholesterol metabolite was found to quantitatively replace this oxysterol in the Cyp46a1−/− mouse. Only minor amounts of other side-chain oxysterols including 22R-, 24R-, 25- and (25R),26-hydroxycholesterols were detected. In line with earlier studies, levels of cholesterol were similar in Cyp46a1−/− and wild type animals. However, the level of the cholesterol precursor, desomsterol, and its parallel metabolite formed via a shut of the mevalonate pathway, 24S,25-epoxycholesterol, were reduced in the Cyp46a1−/− mouse. The reduction in abundance of 24S,25-epoxycholesterol is interesting in light of a recent report indicating that this oxysterol promotes dopaminergic neurogenesis.

Keywords

24S-Hydroxycholesterol
24R-Hydroxycholesterol
24S,25-Epoxycholesterol
Oxysterol
Brain
Cyp46a1

Abbreviations

Cyp
cytochrome P450
ESI
electrospray ionisation
FT
Fourier transform
GP
Girard P reagent
INSIG
insulin induced gene
LC
liquid chromatography
Lxr
liver x receptor
MRM
multiple reaction monitoring
MS
mass spectrometry or mass spectrum
MSn
mass spectrometry with multistage fragmentation
RIC
reconstructed ion chromatogram
RP
reversed phase
SCAP
SREBP cleavage-activating protein
SPE
solid phase extraction
SREBP
sterol regulatory-element binding protein
TLR
Toll-like receptor
wt
wild type

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