Cerebrospinal fluid steroidomics: are bioactive bile acids present in brain?

Area of Science:

• Biochemistry
• Neuroscience
• Metabolomics

Background:

• Cholesterol metabolism is crucial for brain function.
• Bile acid biosynthetic pathways are typically associated with the liver.
• Alterations in cholesterol metabolites are implicated in neurodegenerative diseases like Alzheimer's.

Purpose of the Study:

• To profile free sterol content in human cerebrospinal fluid (CSF).
• To identify and quantify cholesterol metabolites, particularly bile acid intermediates.
• To evaluate the potential of these metabolites to activate liver X receptors (LXRs) and farnesoid X receptor.

Main Methods:

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with charge tagging was employed for sterol profiling.
• Quantification of identified metabolites in CSF samples from six subjects.
• Luciferase reporter assays were used to assess the activation of LXRs by specific cholesterol metabolites.

Main Results:

• The most abundant sterols in CSF were identified as C27 and C24 intermediates of bile acid biosynthesis.
• Key identified metabolites include 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid and 3beta-hydroxycholest-5-en-26-oic acid.
• While 3beta-hydroxycholest-5-en-26-oic acid and 3beta,7alpha-dihydroxycholest-5-en-26-oic acid activated LXR, the major metabolite 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid did not.

Conclusions:

• Bile acid pathway intermediates are unexpectedly prevalent in human CSF.
• The enzyme 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase (HSD3B7) may represent a pathway for deactivating LXR ligands in the brain.
• These findings suggest a significant role for cholesterol metabolites in the etiology of Alzheimer's disease, potentially through LXR modulation.