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Biomolecules 2019, 9(4), 149; https://doi.org/10.3390/biom9040149

Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5

1
Swansea University Medical School, ILS1 Building, Singleton Park, Swansea SA2 8PP, UK
2
Institute for Global Food Security, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, UK
3
Endocrinology Unit, BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
4
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
Received: 6 March 2019 / Revised: 28 March 2019 / Accepted: 2 April 2019 / Published: 13 April 2019
(This article belongs to the Special Issue Lipidomics)
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Abstract

Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography–mass spectrometry (LC–MS) and multistage fragmentation (MSn), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3β-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered. View Full-Text
Keywords: cytochrome P450; CYP7B1; hereditary spastic paraplegia; SPG5; 25-hydroxycholesterol; 7α,25-dihydroxycholesterol; cholestenoic acid; cholesterol; liquid chromatography–mass spectrometry; multistage fragmentation cytochrome P450; CYP7B1; hereditary spastic paraplegia; SPG5; 25-hydroxycholesterol; 7α,25-dihydroxycholesterol; cholestenoic acid; cholesterol; liquid chromatography–mass spectrometry; multistage fragmentation
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Meljon, A.; Crick, P.J.; Yutuc, E.; Yau, J.L.; Seckl, J.R.; Theofilopoulos, S.; Arenas, E.; Wang, Y.; Griffiths, W.J. Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5. Biomolecules 2019, 9, 149.

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