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

ABSTRACT: Cholestane-3?,5?,6?-triol (3?,5?,6?-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 7?-hydroxycholesterol (7?-HC) can also be formed by free radical oxidation of cholesterol. Here we investigate how 3?,5?,6?-triol, 7-OC and 7?-HC are metabolised to bile acids. We show, by monitoring oxysterol metabolites in plasma samples rich in 3?,5?,6?-triol, 7-OC and 7?-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 3?,5?,6?-trihydroxycholanoic, 3?-hydroxy-7-oxochol-5-enoic and 3?,7?-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.

SUBMITTER: Griffiths WJ

PROVIDER: S-EPMC6863434 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Griffiths William J WJ Yutuc Eylan E Abdel-Khalik Jonas J Crick Peter J PJ Hearn Thomas T Dickson Alison A Bigger Brian W BW Hoi-Yee Wu Teresa T Goenka Anu A Ghosh Arunabha A Jones Simon A SA Covey Douglas F DF Ory Daniel S DS Wang Yuqin Y

Free radical biology & medicine 20190419

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 ...[more]

PMID: 31009661

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Project description:Tissue accumulation of 7-dehydrocholesterol (7DHC) is a hallmark of Smith-Lemli-Opitz Syndrome (SLOS), a human inborn error of the cholesterol (CHOL) synthesis pathway. Retinal 7DHC-derived oxysterol formation occurs in the AY9944-induced rat model of SLOS, which exhibits a retinal degeneration characterized by selective loss of photoreceptors and associated functional deficits, Müller cell hypertrophy, and engorgement of the retinal pigment epithelium (RPE) with phagocytic inclusions. We evaluated the relative effects of four 7DHC-derived oxysterols on three retina-derived cell types in culture, with respect to changes in cellular morphology and viability. 661W (photoreceptor-derived) cells, rMC-1 (Müller glia-derived) cells, and normal diploid monkey RPE (mRPE) cells were incubated for 24 h with dose ranges of either 7-ketocholesterol (7kCHOL), 5,9-endoperoxy-cholest-7-en-3β,6α-diol (EPCD), 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), or 4β-hydroxy-7-dehydrocholesterol (4HDHC); CHOL served as a negative control (same dose range), along with appropriate vehicle controls, while staurosporine (Stsp) was used as a positive cytotoxic control. For 661W cells, the rank order of oxysterol potency was: EPCD > 7kCHOL >> DHCEO > 4HDHC ≈ CHOL. EC50 values were higher for confluent vs. subconfluent cultures. 661W cells exhibited much higher sensitivity to EPCD and 7kCHOL than either rMC-1 or mRPE cells, with the latter being the most robust when challenged, either at confluence or in sub-confluent cultures. When tested on rMC-1 and mRPE cells, EPCD was again an order of magnitude more potent than 7kCHOL in compromising cellular viability. Hence, 7DHC-derived oxysterols elicit differential cytotoxicity that is dose-, cell type-, and cell density-dependent. These results are consistent with the observed progressive, photoreceptor-specific retinal degeneration in the rat SLOS model, and support the hypothesis that 7DHC-derived oxysterols are causally linked to that retinal degeneration as well as to SLOS.

Dataset Information

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

Publications

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

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