TY - JOUR
T1 - Metabolism of Non-Enzymatically Derived Oxysterols
T2 - Clues from sterol metabolic disorders
AU - Griffiths, William J
AU - Yutuc, Eylan
AU - Abdel-Khalik, Jonas
AU - Crick, Peter J
AU - Hearn, Thomas
AU - Dickson, Alison
AU - Bigger, Brian W
AU - Hoi-Yee Wu, Teresa
AU - Goenka, Anu
AU - Ghosh, Arunabha
AU - Jones, Simon A
AU - Covey, Douglas F
AU - Ory, Daniel S
AU - Wang, Yuqin
N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2019/11/20
Y1 - 2019/11/20
N2 - 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.
AB - 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.
KW - Biotransformation
KW - Cholestanols/blood
KW - Cholesterol/blood
KW - Cholic Acids/biosynthesis
KW - Chromatography, Liquid
KW - Epoxide Hydrolases/blood
KW - Free Radicals/blood
KW - Humans
KW - Hydroxycholesterols/blood
KW - Hydroxylation
KW - Ketocholesterols/blood
KW - Lysosomal Storage Diseases/blood
KW - Mass Spectrometry
KW - Niemann-Pick Diseases/blood
KW - Oxidation-Reduction
KW - Wolman Disease/blood
U2 - 10.1016/j.freeradbiomed.2019.04.020
DO - 10.1016/j.freeradbiomed.2019.04.020
M3 - Article
C2 - 31009661
SN - 0891-5849
VL - 144
SP - 124
EP - 133
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -
