Journal article 1055 views 112 downloads
Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma
,
Peter J. Crick,
Anna Meljon,
Spyridon Theofilopoulos ,
Jonas Abdel-Khalik,
Eylan Yutuc ,
Josie Parker,
Diane Kelly,
Steven Kelly ,
Ernest Arenas,
Yuqin Wang
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Volume: 1864, Issue: 2, Pages: 191 - 211
Swansea University Authors:
William Griffiths , Spyridon Theofilopoulos , Eylan Yutuc , Josie Parker, Diane Kelly, Steven Kelly , Yuqin Wang
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DOI (Published version): 10.1016/j.bbalip.2018.11.006
Abstract
Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A...
| Published in: | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |
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| ISSN: | 1388-1981 |
| Published: |
Elsevier BV
2019
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa46057 |
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| Abstract: |
Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A1 gene are the cause of the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). Surprisingly, Cyp27a1 knockout mice (Cyp27a1-/-) do not present a CTX phenotype despite generating a similar global pattern of sterols. Using liquid chromatography – mass spectrometry and exploiting a charge-tagging approach for oxysterol analysis we identified over 50 cholesterol metabolites and precursors in the brain and circulation of Cyp27a1-/- mice. Notably, we identified (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids, indicating the presence of an additional sterol 26-hydroxylase in mouse. Importantly, our analysis also revealed elevated levels of 7α-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7α-Hydroxycholest-4-en-3-one is a ligand for the pregnane X receptor (PXR), activation of which is known to up-regulate the expression of CYP3A11, which we confirm has sterol 26-hydroxylase activity. This can explain the formation of (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids; the acid with the former stereochemistry is a liver X receptor (LXR) ligand that increases the number of oculomotor neurons in primary brain cultures. We hereby suggest that a lack of a motor neuron phenotype in some CTX patients and Cyp27a1-/- mice may involve increased levels of 7α-hydroxycholest-4-en-3-one and activation PXR, as well as increased levels of sterol 26-hydroxylase and the production of neuroprotective sterols capable of activating LXR. |
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| Keywords: |
CYP27A1, cerebrotendinous xanthomatosis, oxysterol, cholestenoic acid, brain, mass spectrometry |
| Issue: |
2 |
| Start Page: |
191 |
| End Page: |
211 |