Formation and metabolism of oxysterols and cholestenoic acids found in the mouse circulation: Lessons learnt from deuterium-enrichment experiments and the CYP46A1 transgenic mouse. Issue 195 (December 2019)

• Record Type: Journal Article
• Authors: Crick, Peter J.; Yutuc, Eylan; Abdel-Khalik, Jonas; Saeed, Ahmed; Betsholtz, Christer; Genove, Guillem; Björkhem, Ingemar; Wang, Yuqin; Griffiths, William J.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 195(2019)
• Publication Date: 2019-12
• Subjects: 24S-hydroxycholesterol -- 24S, 25-epoxycholesterol -- CYP46A1 -- Bile acid biosynthesis -- Deuterium-enrichment -- Deuterium-isotope effect -- Liquid chromatography–mass spectrometry -- Derivatisation; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.105475
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Pathway from 24S-HC towards bile acids. Non-cerebral CYP46A1-idipendent biosynthesis of 24R-HC. Different pathways used in the formation of 3β-HCA and 7αH, 3O-CA. Abstract: While the presence and abundance of the major oxysterols and cholestenoic acids in the circulation is well established, minor cholesterol metabolites may also have biological importance and be of value to investigate. In this study by observing the metabolism of deuterium-labelled cholesterol in the pdgfb ret/ret mouse, a mouse model with increased vascular permeability in brain, and by studying the sterol content of plasma from the CYP46A1 transgenic mouse overexpressing the human cholesterol 24S-hydroxylase enzyme we have been able to identify a number of minor cholesterol metabolites found in the circulation, make approximate-quantitative measurements and postulate pathways for their formation. These "proof of principle" data may have relevance when using mouse models to mimic human disease and in respect of the increasing possibility of treating human neurodegenerative diseases with pharmaceuticals designed to enhance the activity of CYP46A1 or by adeno-associated virus delivery of CYP46A1 .