Elsevier

Free Radical Biology and Medicine

Volume 144, 20 November 2019, Pages 124-133
Free Radical Biology and Medicine

Metabolism of Non-Enzymatically Derived Oxysterols: Clues from sterol metabolic disorders,☆☆

https://doi.org/10.1016/j.freeradbiomed.2019.04.020Get rights and content
Under a Creative Commons license
open access

Highlights

  • Free radical derived oxysterols metabolised to unusual bile acids.

  • Metabolism proceeds via novel branches of the acidic pathway.

  • Bile acids with:- 3β,5α,6β-triol; 3β,7β-diol-5-ene or 3β-ol-5-en-7-one in A/B-ring.

  • Unusual bile acids found in plasma from patients with NPC, NPB and LALD.

  • Intermediates in the biosynthesis of unusual bile acids found in plasma.

Abstract

Cholestane-3β,5α,6β-triol (3β,5α,6β-triol) is formed from cholestan-5,6-epoxide (5,6-EC) in a reaction catalysed by cholesterol epoxide hydrolase, following formation of 5,6-EC through free radical oxidation of cholesterol. 7-Oxocholesterol (7-OC) and 7β-hydroxycholesterol (7β-HC) can also be formed by free radical oxidation of cholesterol. Here we investigate how 3β,5α,6β-triol, 7-OC and 7β-HC are metabolised to bile acids. We show, by monitoring oxysterol metabolites in plasma samples rich in 3β,5α,6β-triol, 7-OC and 7β-HC, that these three oxysterols fall into novel branches of the acidic pathway of bile acid biosynthesis becoming (25R)26-hydroxylated then carboxylated, 24-hydroxylated and side-chain shortened to give the final products 3β,5α,6β-trihydroxycholanoic, 3β-hydroxy-7-oxochol-5-enoic and 3β,7β-dihydroxychol-5-enoic acids, respectively. The intermediates in these pathways may be causative of some phenotypical features of, and/or have diagnostic value for, the lysosomal storage diseases, Niemann Pick types C and B and lysosomal acid lipase deficiency. Free radical derived oxysterols are metabolised in human to unusual bile acids via novel branches of the acidic pathway, intermediates in these pathways are observed in plasma.

Keywords

Niemann-Pick disease
Cholesterol/metabolism
Bile acid and salts/biosynthesis
Inborn errors of metabolism
Mass spectrometry
Lipidomics
Free radical

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Swansea Innovations Ltd have licensed derivatisation technology described in this paper to Avanti Polar Lipids Inc. and Cayman Chemical Company.