Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.

Autor: Abdel-Khalik J; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Hearn T; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Dickson AL; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Crick PJ; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Yutuc E; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Austin-Muttitt K; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Bigger BW; Stem Cell & Neurotherapies, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK., Morris AA; Willink Unit, Manchester Centre for Genomic Medicine, Manchester University Hospitals, Manchester, M13 9WL, UK., Shackleton CH; University of California San Francisco (UCSF) Benioff Children's Hospital, Oakland, CA 94609, USA., Clayton PT; Inborn Errors of Metabolism, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK., Iida T; Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajousui, Setagaya, Tokyo, 156-8550, Japan., Sircar R; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA., Rohatgi R; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA., Marschall HU; Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska Academy, Institute of Medicine, Gothenburg, 41345, Sweden., Sjövall J; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden., Björkhem I; Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, 14186, Stockholm, Sweden., Mullins JGL; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK., Griffiths WJ; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK. Electronic address: w.j.griffiths@swansea.ac.uk., Wang Y; Swansea University Medical School, ILS1 Building, Singleton Park, Swansea, SA2 8PP, Wales, UK. Electronic address: y.wang@swansea.ac.uk.
Jazyk: angličtina
Zdroj: The Journal of steroid biochemistry and molecular biology [J Steroid Biochem Mol Biol] 2021 Feb; Vol. 206, pp. 105794. Date of Electronic Publication: 2020 Nov 24.
DOI: 10.1016/j.jsbmb.2020.105794
Abstrakt: 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 Δ 5 -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.
(Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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