Additional pathways of sterol metabolism: evidence from analysis of Cyp27a1-/- mouse brain and plasma

Griffiths, William J., Crick, Peter J., Meljon, Anna, Theofilopoulos, Spyridon, Abdel-Khalik, Jonas, Yutuc, Eylan, Parker, Josie E., Kelly, Diane E., Kelly, Steven L., Arenas, Ernest and Wang, Yuqin 2019. Additional pathways of sterol metabolism: evidence from analysis of Cyp27a1-/- mouse brain and plasma. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 1864 (2) , pp. 191-211. 10.1016/j.bbalip.2018.11.006

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier
ISSN:	1388-1981
Date of First Compliant Deposit:	8 July 2022
Date of Acceptance:	18 November 2018
Last Modified:	24 Aug 2022 13:45
URI:	https://orca.cardiff.ac.uk/id/eprint/151162

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