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Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ong...

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Autores principales: Höflinger, Philip, Hauser, Stefan, Yutuc, Eylan, Hengel, Holger, Griffiths, Lauren, Radelfahr, Florentine, Howell, Owain W., Wang, Yuqin, Connor, Sonja L., Duell, P. Barton, DeBarber, Andrea E., Martus, Peter, Lütjohann, Dieter, Griffiths, William J., Schöls, Ludger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135047/
https://www.ncbi.nlm.nih.gov/pubmed/33891937
http://dx.doi.org/10.1016/j.jlr.2021.100078
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author Höflinger, Philip
Hauser, Stefan
Yutuc, Eylan
Hengel, Holger
Griffiths, Lauren
Radelfahr, Florentine
Howell, Owain W.
Wang, Yuqin
Connor, Sonja L.
Duell, P. Barton
DeBarber, Andrea E.
Martus, Peter
Lütjohann, Dieter
Griffiths, William J.
Schöls, Ludger
author_facet Höflinger, Philip
Hauser, Stefan
Yutuc, Eylan
Hengel, Holger
Griffiths, Lauren
Radelfahr, Florentine
Howell, Owain W.
Wang, Yuqin
Connor, Sonja L.
Duell, P. Barton
DeBarber, Andrea E.
Martus, Peter
Lütjohann, Dieter
Griffiths, William J.
Schöls, Ludger
author_sort Höflinger, Philip
collection PubMed
description Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and cerebrospinal fluid (CSF) of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be highly sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.
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spelling pubmed-81350472021-05-24 Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis Höflinger, Philip Hauser, Stefan Yutuc, Eylan Hengel, Holger Griffiths, Lauren Radelfahr, Florentine Howell, Owain W. Wang, Yuqin Connor, Sonja L. Duell, P. Barton DeBarber, Andrea E. Martus, Peter Lütjohann, Dieter Griffiths, William J. Schöls, Ludger J Lipid Res Patient-oriented and Epidemiological Research Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and cerebrospinal fluid (CSF) of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be highly sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment. American Society for Biochemistry and Molecular Biology 2021-04-20 /pmc/articles/PMC8135047/ /pubmed/33891937 http://dx.doi.org/10.1016/j.jlr.2021.100078 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Patient-oriented and Epidemiological Research
Höflinger, Philip
Hauser, Stefan
Yutuc, Eylan
Hengel, Holger
Griffiths, Lauren
Radelfahr, Florentine
Howell, Owain W.
Wang, Yuqin
Connor, Sonja L.
Duell, P. Barton
DeBarber, Andrea E.
Martus, Peter
Lütjohann, Dieter
Griffiths, William J.
Schöls, Ludger
Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_full Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_fullStr Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_full_unstemmed Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_short Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_sort metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
topic Patient-oriented and Epidemiological Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135047/
https://www.ncbi.nlm.nih.gov/pubmed/33891937
http://dx.doi.org/10.1016/j.jlr.2021.100078
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