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

William J Griffiths; Eylan Yutuc; Jonas Abdel-Khalik; Peter J Crick; Thomas Hearn; Alison Dickson; Brian W Bigger; Teresa Hoi-Yee Wu; Anu Goenka; Arunabha Ghosh; Simon A Jones; Douglas F Covey; Daniel S Ory; Yuqin Wang

doi:10.1016/j.freeradbiomed.2019.04.020

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

William J Griffiths, Eylan Yutuc, Jonas Abdel-Khalik, Peter J Crick, Thomas Hearn, Alison Dickson, Brian W Bigger, Teresa Hoi-Yee Wu, Anu Goenka, Arunabha Ghosh, Simon A Jones, Douglas F Covey, Daniel S Ory, Yuqin Wang

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	124-133
Number of pages	10
Journal	Free Radical Biology and Medicine
Volume	144
DOIs	https://doi.org/10.1016/j.freeradbiomed.2019.04.020
Publication status	Published - 20 Nov 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Biotransformation
Cholestanols/blood
Cholesterol/blood
Cholic Acids/biosynthesis
Chromatography, Liquid
Epoxide Hydrolases/blood
Free Radicals/blood
Humans
Hydroxycholesterols/blood
Hydroxylation
Ketocholesterols/blood
Lysosomal Storage Diseases/blood
Mass Spectrometry
Niemann-Pick Diseases/blood
Oxidation-Reduction
Wolman Disease/blood

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10.1016/j.freeradbiomed.2019.04.020

Cite this

Griffiths, W. J., Yutuc, E., Abdel-Khalik, J., Crick, P. J., Hearn, T., Dickson, A., Bigger, B. W., Hoi-Yee Wu, T., Goenka, A., Ghosh, A., Jones, S. A., Covey, D. F., Ory, D. S., & Wang, Y. (2019). Metabolism of Non-Enzymatically Derived Oxysterols: Clues from sterol metabolic disorders. Free Radical Biology and Medicine, 144, 124-133. https://doi.org/10.1016/j.freeradbiomed.2019.04.020

@article{2605f54903ca436bb3f253398944f267,

title = "Metabolism of Non-Enzymatically Derived Oxysterols: Clues from sterol metabolic disorders",

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 = "Biotransformation, Cholestanols/blood, Cholesterol/blood, Cholic Acids/biosynthesis, Chromatography, Liquid, Epoxide Hydrolases/blood, Free Radicals/blood, Humans, Hydroxycholesterols/blood, Hydroxylation, Ketocholesterols/blood, Lysosomal Storage Diseases/blood, Mass Spectrometry, Niemann-Pick Diseases/blood, Oxidation-Reduction, Wolman Disease/blood",

author = "Griffiths, \{William J\} and Eylan Yutuc and Jonas Abdel-Khalik and Crick, \{Peter J\} and Thomas Hearn and Alison Dickson and Bigger, \{Brian W\} and \{Hoi-Yee Wu\}, Teresa and Anu Goenka and Arunabha Ghosh and Jones, \{Simon A\} and Covey, \{Douglas F\} and Ory, \{Daniel S\} and Yuqin Wang",

year = "2019",

month = nov,

day = "20",

doi = "10.1016/j.freeradbiomed.2019.04.020",

language = "English",

volume = "144",

pages = "124--133",

journal = "Free Radical Biology and Medicine",

issn = "0891-5849",

publisher = "Elsevier Inc.",

}

Griffiths, WJ, Yutuc, E, Abdel-Khalik, J, Crick, PJ, Hearn, T, Dickson, A, Bigger, BW, Hoi-Yee Wu, T, Goenka, A, Ghosh, A, Jones, SA, Covey, DF, Ory, DS & Wang, Y 2019, 'Metabolism of Non-Enzymatically Derived Oxysterols: Clues from sterol metabolic disorders', Free Radical Biology and Medicine, vol. 144, pp. 124-133. https://doi.org/10.1016/j.freeradbiomed.2019.04.020

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

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

UR - https://www.scopus.com/pages/publications/85065046469

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 -

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

Abstract

UN SDGs

Keywords

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