Allied Journal of Medical Research

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Lipidomics Impact Factor

Deficiency in cytochrome P450 (CYP) 7B1, also referred to as oxysterol 7α-hydroxylase, in humans results in hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to disease . SPG5 is medically characterized by loss of motor neurons within the pyramidal tract . In an attempt to realize a far better understanding of the elemental biochemistry of this disorder, we've extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to incorporate , amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels don't differ between wild-type (wt) and knockout mice, we find, employing a charge-tagging methodology together with liquid chromatography–mass spectrometry (LC–MS) and multistage fragmentation (MSn), that there's 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 propose 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 doesn't show a motor defect; whether the defect in humans may be a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered.

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