No Cover Image

Journal article 105 views 17 downloads

Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates / Jonas Abdel-Khalik; Tom Hearn; Alison Dickson; Peter Crick; Eylan Yutuc; Karl Austin-Muttitt; Brian W. Bigger; Andrew A. Morris; Cedric H. Shackleton; Peter T. Clayton; Takashi Iida; Ria Sircar; Rajat Rohatgi; Hanns-Ulrich Marschall; Jan Sjövall; Ingemar Björkhem; Jonathan Mullins; William Griffiths; Yuqin Wang

The Journal of Steroid Biochemistry and Molecular Biology, Volume: 206, Start page: 105794

Swansea University Authors: Jonas, Abdel-Khalik, Tom, Hearn, Alison, Dickson, Peter, Crick, Eylan, Yutuc, Karl, Austin-Muttitt, Jonathan, Mullins, William, Griffiths, Yuqin, Wang

  • 55690.VOR.pdf

    PDF | Version of Record

    © 2020 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 (CC BY) License.

    Download (7.67MB)

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 s...

Full description

Published in: The Journal of Steroid Biochemistry and Molecular Biology
ISSN: 0960-0760
Published: Elsevier BV 2021
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa55690
Tags: Add Tag
No Tags, Be the first to tag this record!
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.
Keywords: sterol; oxysterol; bile acid7-dehydrocholesterol; Smith-Lemli-Opitz syndrome; high-performance liquid chromatography; mass spectrometry; Hedgehog signalling pathway
College: Swansea University Medical School
Start Page: 105794