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

Autor: Anna Meljon, Ernest Arenas, Eylan Yutuc, Joyce L.W. Yau, William J. Griffiths, Spyridon Theofilopoulos, Peter J. Crick, Jonathan R. Seckl, Yuqin Wang
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
7α
25-dihydroxycholesterol
medicine.medical_specialty
CYP7B1
Oxysterol
cytochrome P450
Hereditary spastic paraplegia
25-hydroxycholesterol
Cytochrome P450 Family 7
lcsh:QR1-502
SPG5
liquid chromatography–mass spectrometry
Biochemistry
lcsh:Microbiology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
medicine
Animals
hereditary spastic paraplegia
Molecular Biology
biology
Spastic Paraplegia
Hereditary
Chemistry
Cholesterol
Communication
Brain
cholesterol
multistage fragmentation
Cytochrome P450
medicine.disease
Hydroxycholesterols
Sterol
cholestenoic acid
030104 developmental biology
Endocrinology
Steroid Hydroxylases
Knockout mouse
biology.protein
lipids (amino acids
peptides
and proteins)
030217 neurology & neurosurgery
Homeostasis
Zdroj: Biomolecules, Vol 9, Iss 4, p 149 (2019)
Biomolecules
Meljon, A, Crick, P J, Yutuc, E, Yau, J L, Seckl, J R, Theofilopoulos, S, Arenas, E, Wang, Y & Griffiths, W J 2019, ' Mining for Oxysterols in Cyp7b1-/-Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5. ', Biomolecules, vol. 9, no. 4 . https://doi.org/10.3390/biom9040149
Meljon, A, Crick, P J, Yutuc, E, Yau, J L, Seckl, J R, Theofilopoulos, S, Arenas, E, Wang, Y & Griffiths, W J 2019, ' Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5 ', Biomolecules, vol. 9, no. 4, pp. 149 . https://doi.org/10.3390/biom9040149
ISSN: 2218-273X
DOI: 10.3390/biom9040149
Popis: 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.
Databáze: OpenAIRE
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