On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO

Björkhem, Ingemar; Diczfalusy, Ulf; Lövgren‐Sandblom, Anita; Starck, Lena; Jönsson, Malin; Tallman, Keri A.; Schirmer, Henrik; Ousager, Lilian Bomme; Crick, Peter J.; Wang, Yuqin; Griffiths, William J.; Guengerich, F. Peter

doi:10.1194/jlr.p048603

Cited by 47 publications

(44 citation statements)

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“…Moreover, 7-KC was also high in patients with CTX and SLO syndrome, as has been previously described (37)(38)(39), but it is interesting to note that all CTX patients showed high plasma levels not only of 7-KC but also of CT ( Fig. 3D ), data not previously described, and a very big peak of another triol presumably of 3 a ,7 a ,12 a -trihydroxycoprostane ( Fig.…”

Section: Sensitivity and Specifi Citysupporting

confidence: 65%

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Pajares

Arias

García‐Villoria

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org Niemann-Pick type C (NPC; MIM#257220) is a progressive neurodegenerative disease caused by a disorder in the intracellular traffi cking of cholesterol that leads to a lysosomal/endosomal accumulation of unesterifi ed cholesterol and glycolipids in many tissues ( 1-3 ). The detection of free cholesterol accumulation by fi lipin staining in fibroblasts has been for many years the gold standard methodology for the biochemical diagnosis of the disease. This method has good sensitivity and specifi city. However, juvenile or adult onset forms sometimes present interpretation diffi culties ( 4 ). In addition, the method involves an invasive skin biopsy and the culture of fi broblasts that requires several weeks for the cellular growth, which delays the diagnosis. Some studies in cellular and animal models showed a correlation between lipid accumulation and cellular oxidative stress that produces an increase of reactive oxygen species and lipid peroxidation ( 5-8 ). In the NPC murine model, an increase of two oxysterols, cholestane-3 b ,5 a ,6 b -triol (CT) and 7-ketocholesterol (7-KC), has been observed ( 8 ). This evidence was later confi rmed in NPC patients (8)(9)(10)(11)(12)(13), showing a correlation between the oxysterol profi le and the age of onset and severity of the disease ( 8,14 ). Moreover, CT specifi cally has been found to be increased in NPC disease compared with other lysosomal and neurodegenerative diseases ( 8 ). These results Abstract Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterifi ed cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3 ␤ ,5 ␣ ,6 ␤ -triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specifi city of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 pa- 26,26,26,27,27, ; AUC, area under receiver-operating characteristic curve; BHT, butylhydroxytoluene; CI, confi dence interval; CT, cholestane-3 b ,5 a ,6 b -triol; 5 a ,26,26,26,27,27, ; CTX, cerebrotendinous xanthomatosis; % CV, percentage coeffi cient of variation; LAL, lysosomal acid lipase; LOD, limit of detection; LOQ, limit of quantifi cation; LSD, lysosomal storage disease; MRM, multiple reaction monitoring; NPC, Niemann-Pick type C; ROC, receiver-operating characteristic; SLO, Smith-Lemli-Opitz.

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Section: Sensitivity and Specifi Citysupporting

confidence: 65%

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Pajares

Arias

García‐Villoria

et al. 2015

Journal of Lipid Research

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“…Helium was used as the carrier gas, maintained at a constant fl ow rate of 1.5 ml/min. The GC temperature program was as follows: initial temperature 70°C for 1 min; program from 70 to 130°C at a rate of 50°C/min, hold for 1 min at 130°C; program SLOS and/or cerebrotendinous xanthomatosis ( 12,21 ), providing support for such enzymatic transformation in vivo. Desmosterol, an alternate immediate precursor of cholesterol, contains a double bond at C24 and we hypothesized that, analogous to the reactions of 7-dehydrocholesterol and P450 7A1, desmosterol could be a substrate for P450 46A1, leading to 24,25-epoxycholesterol, 24-ketocholesterol, and/or some side-chain hydroxylated product.…”

Section: Gc-msmentioning

confidence: 99%

Oxidation of 7-dehydrocholesterol and desmosterol by human cytochrome P450 46A1

Goyal

Xiao

Porter

et al. 2014

Journal of Lipid Research

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“…Besides NP-C disease, two recent studies, based on the determination of 7-KC alone, showed its increase in NP-B disease and in SLOS, two inherited disorders due to deficient activity of the lysosmal enzyme sphingomyelinase and of 7-dehydrocholesterol reductase, respectively ( 15,16 ). A further study, showed that both 7-KC and C-triol were elevated in NP-B patients ( 14 ).…”

Section: Patients' Resultsmentioning

confidence: 99%

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Boenzi

Deodato

Taurisano

et al. 2016

Journal of Lipid Research

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On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO

Cited by 47 publications

References 20 publications

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Oxidation of 7-dehydrocholesterol and desmosterol by human cytochrome P450 46A1

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

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