Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
AbstractDeficiency 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
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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.
Meljon A, Crick PJ, Yutuc E, Yau JL, Seckl JR, Theofilopoulos S, Arenas E, Wang Y, Griffiths WJ. Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5. Biomolecules. 2019; 9(4):149.Chicago/Turabian Style
Meljon, Anna; Crick, Peter J.; Yutuc, Eylan; Yau, Joyce L.; Seckl, Jonathan R.; Theofilopoulos, Spyridon; Arenas, Ernest; Wang, Yuqin; Griffiths, William J. 2019. "Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5." Biomolecules 9, no. 4: 149.
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