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Bile Acid Biosynthesis in Smith-Lemli-Opitz Syndrome Bypassing Cholesterol: Potential Importance of Pathway Intermediates

Abdel-Khalik, J; Hearn, T; Dickson, AL; Crick, PJ; Yutuc, E; Austin-Muttit, K; Bigger, BW; ... Wang, Y; + view all (2020) Bile Acid Biosynthesis in Smith-Lemli-Opitz Syndrome Bypassing Cholesterol: Potential Importance of Pathway Intermediates. The Journal of Steroid Biochemistry and Molecular Biology , Article 105794. 10.1016/j.jsbmb.2020.105794. (In press). Green open access

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Abstract

Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.

Type: Article
Title: Bile Acid Biosynthesis in Smith-Lemli-Opitz Syndrome Bypassing Cholesterol: Potential Importance of Pathway Intermediates
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jsbmb.2020.105794
Publisher version: https://doi.org/10.1016/j.jsbmb.2020.105794
Language: English
Additional information: This is an open access article under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
Keywords: sterol; oxysterol; bile acid; 7-dehydrocholesterol; Smith-Lemli-Opitz syndrome; high-performance liquid chromatography; mass spectrometry; Hedgehog signalling pathway
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10116843
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