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Defective cholesterol metabolism in amyotrophic lateral sclerosis

As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 differ...

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Autores principales: Abdel-Khalik, Jonas, Yutuc, Eylan, Crick, Peter J., Gustafsson, Jan-Åke, Warner, Margaret, Roman, Gustavo, Talbot, Kevin, Gray, Elizabeth, Griffiths, William J., Turner, Martin R., Wang, Yuqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Biochemistry and Molecular Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234729/
https://www.ncbi.nlm.nih.gov/pubmed/27811233
http://dx.doi.org/10.1194/jlr.P071639
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author Abdel-Khalik, Jonas
Yutuc, Eylan
Crick, Peter J.
Gustafsson, Jan-Åke
Warner, Margaret
Roman, Gustavo
Talbot, Kevin
Gray, Elizabeth
Griffiths, William J.
Turner, Martin R.
Wang, Yuqin
author_facet Abdel-Khalik, Jonas
Yutuc, Eylan
Crick, Peter J.
Gustafsson, Jan-Åke
Warner, Margaret
Roman, Gustavo
Talbot, Kevin
Gray, Elizabeth
Griffiths, William J.
Turner, Martin R.
Wang, Yuqin
author_sort Abdel-Khalik, Jonas
collection PubMed
description As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid.
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spelling pubmed-52347292017-01-25 Defective cholesterol metabolism in amyotrophic lateral sclerosis Abdel-Khalik, Jonas Yutuc, Eylan Crick, Peter J. Gustafsson, Jan-Åke Warner, Margaret Roman, Gustavo Talbot, Kevin Gray, Elizabeth Griffiths, William J. Turner, Martin R. Wang, Yuqin J Lipid Res Patient-Oriented and Epidemiological Research As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid. The American Society for Biochemistry and Molecular Biology 2017-01 2016-12-29 /pmc/articles/PMC5234729/ /pubmed/27811233 http://dx.doi.org/10.1194/jlr.P071639 Text en Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc. http://creativecommons.org/licenses/by/4.0/ Author’s Choice—Final version free via Creative Commons CC-BY license.
spellingShingle Patient-Oriented and Epidemiological Research
Abdel-Khalik, Jonas
Yutuc, Eylan
Crick, Peter J.
Gustafsson, Jan-Åke
Warner, Margaret
Roman, Gustavo
Talbot, Kevin
Gray, Elizabeth
Griffiths, William J.
Turner, Martin R.
Wang, Yuqin
Defective cholesterol metabolism in amyotrophic lateral sclerosis
title Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_full Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_fullStr Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_full_unstemmed Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_short Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_sort defective cholesterol metabolism in amyotrophic lateral sclerosis
topic Patient-Oriented and Epidemiological Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234729/
https://www.ncbi.nlm.nih.gov/pubmed/27811233
http://dx.doi.org/10.1194/jlr.P071639
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