Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterolCitation formats

  • External authors:
  • Jonas Abdel-Khalik
  • Thomas Hearn
  • Alison L Dickson
  • Peter J Crick
  • Eylan Yutuc
  • Karl Austin-Muttitt
  • Andrew A Morris
  • Cedric H Shackleton
  • Peter T Clayton
  • Takashi Iida
  • Ria Sircar
  • Rajat Rohatgi
  • Hanns-Ulrich Marschall
  • Jan Sjövall
  • Ingemar Björkhem
  • Jonathan G L Mullins
  • William J Griffiths
  • Yuqin Wang

Standard

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

In: The Journal of steroid biochemistry and molecular biology, Vol. 206, 105794, 01.02.2021.

Research output: Contribution to journalArticlepeer-review

Harvard

Abdel-Khalik, J, Hearn, T, Dickson, AL, Crick, PJ, Yutuc, E, Austin-Muttitt, K, Bigger, BW, Morris, AA, Shackleton, CH, Clayton, PT, Iida, T, Sircar, R, Rohatgi, R, Marschall, H-U, Sjövall, J, Björkhem, I, Mullins, JGL, Griffiths, WJ & Wang, Y 2021, 'Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates', The Journal of steroid biochemistry and molecular biology, vol. 206, 105794. https://doi.org/10.1016/j.jsbmb.2020.105794

APA

Abdel-Khalik, J., Hearn, T., Dickson, A. L., Crick, P. J., Yutuc, E., Austin-Muttitt, K., Bigger, B. W., Morris, A. A., Shackleton, C. H., Clayton, P. T., Iida, T., Sircar, R., Rohatgi, R., Marschall, H-U., Sjövall, J., Björkhem, I., Mullins, J. G. L., Griffiths, W. J., & Wang, Y. (2021). Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates. The Journal of steroid biochemistry and molecular biology, 206, [105794]. https://doi.org/10.1016/j.jsbmb.2020.105794

Vancouver

Abdel-Khalik J, Hearn T, Dickson AL, Crick PJ, Yutuc E, Austin-Muttitt K et al. Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates. The Journal of steroid biochemistry and molecular biology. 2021 Feb 1;206. 105794. https://doi.org/10.1016/j.jsbmb.2020.105794

Author

Abdel-Khalik, Jonas ; Hearn, Thomas ; Dickson, Alison L ; Crick, Peter J ; Yutuc, Eylan ; Austin-Muttitt, Karl ; Bigger, Brian W ; Morris, Andrew A ; Shackleton, Cedric H ; Clayton, Peter T ; Iida, Takashi ; Sircar, Ria ; Rohatgi, Rajat ; Marschall, Hanns-Ulrich ; Sjövall, Jan ; Björkhem, Ingemar ; Mullins, Jonathan G L ; Griffiths, William J ; Wang, Yuqin. / Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol : Potential importance of pathway intermediates. In: The Journal of steroid biochemistry and molecular biology. 2021 ; Vol. 206.

Bibtex

@article{a7c604158f16433ca0f6cfbbdde9e41e,
title = "Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates",
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 = "7-dehydrocholesterol, Bile acid, Hedgehog signalling pathway, High-Performance liquid chromatography, Mass spectrometry, Oxysterol, Smith-Lemli-Opitz syndrome, Sterol",
author = "Jonas Abdel-Khalik and Thomas Hearn and Dickson, {Alison L} and Crick, {Peter J} and Eylan Yutuc and Karl Austin-Muttitt and Bigger, {Brian W} and Morris, {Andrew A} and Shackleton, {Cedric H} and Clayton, {Peter T} and Takashi Iida and Ria Sircar and Rajat Rohatgi and Hanns-Ulrich Marschall and Jan Sj{\"o}vall and Ingemar Bj{\"o}rkhem and Mullins, {Jonathan G L} and Griffiths, {William J} and Yuqin Wang",
note = "Funding Information: This work was supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC, grant numbers BB/I001735/1 and BB/N015932/1 to WJG, BB/L001942/1 to YW); the European Union through European Structural Funds (ESF), as part of the Welsh Government funded Academic Expertise for Business project (to WJG and YW); the Swedish Science Council (to IB); and in the US by NIH/NIGMS (GM106078 to RR); and NIH (5R01HD053036to CHS). ALD was supported via a KESS2 award in association with Markes International from the Welsh Government and the European Social Fund. JAK was supported by a PhD studentship from Imperial College Healthcare Charities. KA-M was supported by a PhD studentship from Moleculomics Ltd. Deidentified amniotic fluid samples from Kennedy Krieger Biochemical Genetics Laboratory were provided courtesy of Richard Kelley and Lisa Kratz. Control urine samples were kindly provided by Lisa Bastin, Joint Clinical Research Facility, Swansea University / ABMU Local Health Board. The molecular docking was undertaken using the Supercomputing Wales research facility. Dr Peter Grosshans and Steve Smith of Markes International are thanked for helpful discussions. Members of the European Network for Oxysterol Research (ENOR, http://oxysterols.com/) are thanked for informative discussions. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = feb,
day = "1",
doi = "10.1016/j.jsbmb.2020.105794",
language = "English",
volume = "206",
journal = "Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol

T2 - Potential importance of pathway intermediates

AU - Abdel-Khalik, Jonas

AU - Hearn, Thomas

AU - Dickson, Alison L

AU - Crick, Peter J

AU - Yutuc, Eylan

AU - Austin-Muttitt, Karl

AU - Bigger, Brian W

AU - Morris, Andrew A

AU - Shackleton, Cedric H

AU - Clayton, Peter T

AU - Iida, Takashi

AU - Sircar, Ria

AU - Rohatgi, Rajat

AU - Marschall, Hanns-Ulrich

AU - Sjövall, Jan

AU - Björkhem, Ingemar

AU - Mullins, Jonathan G L

AU - Griffiths, William J

AU - Wang, Yuqin

N1 - Funding Information: This work was supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC, grant numbers BB/I001735/1 and BB/N015932/1 to WJG, BB/L001942/1 to YW); the European Union through European Structural Funds (ESF), as part of the Welsh Government funded Academic Expertise for Business project (to WJG and YW); the Swedish Science Council (to IB); and in the US by NIH/NIGMS (GM106078 to RR); and NIH (5R01HD053036to CHS). ALD was supported via a KESS2 award in association with Markes International from the Welsh Government and the European Social Fund. JAK was supported by a PhD studentship from Imperial College Healthcare Charities. KA-M was supported by a PhD studentship from Moleculomics Ltd. Deidentified amniotic fluid samples from Kennedy Krieger Biochemical Genetics Laboratory were provided courtesy of Richard Kelley and Lisa Kratz. Control urine samples were kindly provided by Lisa Bastin, Joint Clinical Research Facility, Swansea University / ABMU Local Health Board. The molecular docking was undertaken using the Supercomputing Wales research facility. Dr Peter Grosshans and Steve Smith of Markes International are thanked for helpful discussions. Members of the European Network for Oxysterol Research (ENOR, http://oxysterols.com/) are thanked for informative discussions. Publisher Copyright: © 2020 The Authors

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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.

AB - 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.

KW - 7-dehydrocholesterol

KW - Bile acid

KW - Hedgehog signalling pathway

KW - High-Performance liquid chromatography

KW - Mass spectrometry

KW - Oxysterol

KW - Smith-Lemli-Opitz syndrome

KW - Sterol

U2 - 10.1016/j.jsbmb.2020.105794

DO - 10.1016/j.jsbmb.2020.105794

M3 - Article

C2 - 33246156

VL - 206

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

M1 - 105794

ER -