Crick, Peter, J., Griffiths, William, J., Zhang, Juan, Beibel, Martin, Abdel-Khalik, Jonas, Kuhle, Jens, Sailer, Andreas and Wang, Yuqin (2016) Reduced plasma levels of 25‐hydroxycholesterol and increased CSF levels of bile acid precursors in multiple sclerosis patients. Molecular Neurobiology. ISSN 0893-7648; 1559-1182

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune, inflammatory
disease of the central nervous system (CNS).We have
measured the levels of over 20 non-esterified sterols in plasma
and cerebrospinal fluid (CSF) from patients suffering from
MS, inflammatory CNS disease, neurodegenerative disease
and control patients. Analysis was performed following
enzyme-assisted derivatisation by liquid chromatography–
mass spectrometry (LC–MS) exploiting multistage fragmentation
(MSn). We found increased concentrations of bile acid
precursors in CSF from each of the disease states and that
patients with inflammatory CNS disease classified as
suspected autoimmune disease or of unknown aetiology also
showed elevated concentrations of 25-hydroxycholestertol
(25-HC, P < 0.05) in CSF. Cholesterol concentrations in
CSF were not changed except for patients diagnosed with
amyotrophic lateral sclerosis (P < 0.01) or pathogen-based
infections of the CNS (P < 0.05) where they were elevated.
In plasma, we found that 25-HC (P < 0.01), (25R)26-
hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-
3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05)
were reduced in relapsing-remitting MS (RRMS) patients
compared to controls. The pattern of reduced plasma levels
of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to
RRMS. In summary, in plasma, we find that the concentration
of 25-HC in RRMS patients is significantly lower than in
controls. This is consistent with the hypothesis that a lower
propensity of macrophages to synthesise 25-HC will result in
reduced negative feedback by 25-HC on IL-1 family cytokine
production and exacerbated MS. In CSF, we find that the
dominating metabolites reflect the acidic pathway of bile acid
biosynthesis and the elevated levels of these in CNS disease is
likely to reflect cholesterol release as a result of demyelination
or neuronal death. 25-HC is elevated in patients with inflammatory
CNS disease probably as a consequence of upregulation
of the type 1 interferon-stimulated gene cholesterol
25-hydroxylase in macrophages.

Item Type:	Article
Keywords:	oxysterol, lipid, CH25H, multiple sclerosis
Date Deposited:	01 Feb 2017 00:45
Last Modified:	01 Feb 2017 00:45
URI:	https://oak.novartis.com/id/eprint/28156