ArticleBiochimica et biophysica acta. Molecular and cell biology of lipids2019
Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1-/- mouse brain and plasma.
Article in Biochimica et biophysica acta. Molecular and cell biology of lipids, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 42 citations in OpenAlex.
- Molecular dynamics, docking and quantum calculations reveal conformational changes influenced by CYP271A amino acid mutations related to cerebrotendinous xanthomatosis.Scientific reports · 2025Article
- Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation.Journal of xenobiotics · 2025Review
- Recent advances in gut microbiota metabolite regulation of hepatic pregnane X receptor.Frontiers in immunology · 2025Review
- Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion.Cardiovascular diabetology · 2023Article
- Filarial DAF-12 sense the host serum to resume iL3 development during infection.PLoS pathogens · 2023Article
- Cholesterol metabolism: from lipidomics to immunology.Journal of lipid research · 2022Review
- Identification of unusual oxysterols biosynthesised in human pregnancy by charge-tagging and liquid chromatography - mass spectrometry.Frontiers in endocrinology · 2022Article
- Nuclear Receptors and Lipid Sensing.Advances in experimental medicine and biology · 2022Article
- Cholesterol metabolism pathways - are the intermediates more important than the products?The FEBS journal · 2021Review
- Oxysterols as lipid mediators: Their biosynthetic genes, enzymes and metabolites.Prostaglandins & other lipid mediators · 2020Review
- Localization of sterols and oxysterols in mouse brain reveals distinct spatial cholesterol metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The Biosynthesis of Enzymatically Oxidized Lipids.Frontiers in endocrinology · 2020Review
- Formation and metabolism of oxysterols and cholestenoic acids found in the mouse circulation: Lessons learnt from deuterium-enrichment experiments and the CYP46A1 transgenic mouse.The Journal of steroid biochemistry and molecular biology · 2019Article
- Article
- Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis.Journal of lipid research · 2019Article
- The acidic pathway of bile acid synthesis: Not just an alternative pathwayLiver research (Beijing, China) · 2019Article
- Oxysterol research: a brief review.Biochemical Society transactions · 2019Review
- Mining for Oxysterols inBiomolecules · 2019Article
- Concentrations of bile acid precursors in cerebrospinal fluid of Alzheimer's disease patients.Free radical biology & medicine · 2019Article
- Developing an Enzyme-Assisted Derivatization Method for Analysis of CMolecules (Basel, Switzerland) · 2019Article
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11 authors at 2 institutions in 2 countries.
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Abstract
Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A1 gene are the cause of the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). Surprisingly, Cyp27a1 knockout mice (Cyp27a1-/-) do not present a CTX phenotype despite generating a similar global pattern of sterols. Using liquid chromatography - mass spectrometry and exploiting a charge-tagging approach for oxysterol analysis we identified over 50 cholesterol metabolites and precursors in the brain and circulation of Cyp27a1-/- mice. Notably, we identified (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids, indicating the presence of an additional sterol 26-hydroxylase in mouse. Importantly, our analysis also revealed elevated levels of 7α-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7α-Hydroxycholest-4-en-3-one is a ligand for the pregnane X receptor (PXR), activation of which is known to up-regulate the expression of CYP3A11, which we confirm has sterol 26-hydroxylase activity. This can explain the formation of (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids; the acid with the former stereochemistry is a liver X receptor (LXR) ligand that increases the number of oculomotor neurons in primary brain cultures. We hereby suggest that a lack of a motor neuron phenotype in some CTX patients and Cyp27a1-/- mice may involve increased levels of 7α-hydroxycholest-4-en-3-one and activation PXR, as well as increased levels of sterol 26-hydroxylase and the production of neuroprotective sterols capable of activating LXR.
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