| Cholesterol metabolism: the main pathway acting downstream of cytochrome P450 oxidoreductase in skeletal development of the limb. | |
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MedLine Citation:
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PMID: 19273610 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for all microsomal cytochrome P450 enzymes, which catalyze the metabolism of a wide spectrum of xenobiotic and endobiotic compounds. Point mutations in POR have been found recently in patients with Antley-Bixler-like syndrome, which includes limb skeletal defects. In order to study P450 function during limb and skeletal development, we deleted POR specifically in mouse limb bud mesenchyme. Forelimbs and hind limbs in conditional knockout (CKO) mice were short with thin skeletal elements and fused joints. POR deletion occurred earlier in forelimbs than in hind limbs, leading additionally to soft tissue syndactyly and loss of wrist elements and phalanges due to changes in growth, cell death, and skeletal segmentation. Transcriptional analysis of E12.5 mouse forelimb buds demonstrated the expression of P450s involved in retinoic acid, cholesterol, and arachidonic acid metabolism. Biochemical analysis of CKO limbs confirmed retinoic acid excess. In CKO limbs, expression of genes throughout the whole cholesterol biosynthetic pathway was upregulated, and cholesterol deficiency can explain most aspects of the phenotype. Thus, cellular POR-dependent cholesterol synthesis is essential during limb and skeletal development. Modulation of P450 activity could contribute to susceptibility of the embryo and developing organs to teratogenesis. |
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Authors:
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Katy Schmidt; Catherine Hughes; J A Chudek; Simon R Goodyear; Richard M Aspden; Richard Talbot; Thomas E Gundersen; Rune Blomhoff; Colin Henderson; C Roland Wolf; Cheryll Tickle |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-09 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 29 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-05-04 Completed Date: 2009-06-04 Revised Date: 2010-09-23 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 2716-29 Citation Subset: IM |
Affiliation:
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Division of Cell and Developmental Biology, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom. k.schmidt@bristol.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antley-Bixler Syndrome Phenotype / enzymology, genetics, pathology Bone and Bones / abnormalities*, anatomy & histology, embryology*, enzymology Cholesterol / metabolism* Chondrogenesis / physiology Embryo, Mammalian / anatomy & histology, physiology Extremities / anatomy & histology, embryology*, pathology Humans Limb Deformities, Congenital* / enzymology, genetics, pathology Mice Mice, Inbred C57BL Mice, Knockout NADPH-Ferrihemoprotein Reductase / genetics, metabolism* Oligonucleotide Array Sequence Analysis Phenotype Signal Transduction / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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072523//Wellcome Trust; C4639/A5661//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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57-88-5/Cholesterol; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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