Document Detail


Cerebrospinal fluid steroidomics: are bioactive bile acids present in brain?
MedLine Citation:
PMID:  19996111     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study we have profiled the free sterol content of cerebrospinal fluid by a combination of charge tagging and liquid chromatography-tandem mass spectrometry. Surprisingly, the most abundant cholesterol metabolites were found to be C(27) and C(24) intermediates of the bile acid biosynthetic pathways with structures corresponding to 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid (7.170 +/- 2.826 ng/ml, mean +/- S.D., six subjects), 3beta-hydroxycholest-5-en-26-oic acid (0.416 +/- 0.193 ng/ml), 7alpha,x-dihydroxy-3-oxocholest-4-en-26-oic acid (1.330 +/- 0.543 ng/ml), and 7alpha-hydroxy-3-oxochol-4-en-24-oic acid (0.172 +/- 0.085 ng/ml), and the C(26) sterol 7alpha-hydroxy-26-norcholest-4-ene-3,x-dione (0.204 +/- 0.083 ng/ml), where x is an oxygen atom either on the CD rings or more likely on the C-17 side chain. The ability of intermediates of the bile acid biosynthetic pathways to activate the liver X receptors (LXRs) and the farnesoid X receptor was also evaluated. The acidic cholesterol metabolites 3beta-hydroxycholest-5-en-26-oic acid and 3beta,7alpha-dihydroxycholest-5-en-26-oic acid were found to activate LXR in a luciferase assay, but the major metabolite identified in this study, i.e. 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid, was not an LXR ligand. 7Alpha-hydroxy-3-oxocholest-4-en-26-oic acid is formed from 3beta,7alpha-dihydroxycholest-5-en-26-oic acid in a reaction catalyzed by 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase (HSD3B7), which may thus represent a deactivation pathway of LXR ligands in brain. Significantly, LXR activation has been found to reduce the symptoms of Alzheimer disease (Fan, J., Donkin, J., and Wellington C. (2009) Biofactors 35, 239-248); thus, cholesterol metabolites may play an important role in the etiology of Alzheimer disease.
Authors:
Michael Ogundare; Spyridon Theofilopoulos; Andrew Lockhart; Leslie J Hall; Ernest Arenas; Jan Sjövall; A Gareth Brenton; Yuqin Wang; William J Griffiths
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-07
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-08     Completed Date:  2010-05-11     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4666-79     Citation Subset:  IM    
Affiliation:
Institute of Mass Spectrometry, School of Medicine, Grove Building, Swansea University, Singleton Park, Swansea SA2 8PP, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Bile Acids and Salts / metabolism*
Brain / metabolism*
Cerebrospinal Fluid / metabolism*
Chenodeoxycholic Acid / analogs & derivatives
Chromatography, High Pressure Liquid
Humans
Mass Spectrometry
Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
Orphan Nuclear Receptors / metabolism
Protein Binding
Receptors, Cytoplasmic and Nuclear / metabolism
Retinoid X Receptors / metabolism
Sterols / metabolism*
Grant Support
ID/Acronym/Agency:
BBC5113561//Biotechnology and Biological Sciences Research Council; BBC5157712//Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Nuclear Receptor Subfamily 4, Group A, Member 2; 0/Orphan Nuclear Receptors; 0/Receptors, Cytoplasmic and Nuclear; 0/Retinoid X Receptors; 0/Sterols; 0/farnesoid X-activated receptor; 0/liver X receptor; 474-25-9/Chenodeoxycholic Acid
Comments/Corrections

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