Cholesterol metabolism: the main pathway acting downstream of cytochrome P450 oxidoreductase in skeletal development of the limb
Open accessAbstract
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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Tissue-specific POR knockout in the limb bud mesenchyme of mice induces the expression of genes throughout the cholesterol biosynthetic pathway, suggesting that cholesterol deficiency could explain the skeletal phenotypes.
“First, tissue-specific POR knockout in the limb bud mesenchyme of mice induces the expression of genes throughout the cholesterol biosynthetic pathway, suggesting that cholesterol deficiency could explain the skeletal phenotypes (342).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [342]
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References 100 · Cited by 61
- Authors
- Schmidt, K., Hughes, C., Chudek, J. A., Goodyear, S. R., Aspden, R. M., Talbot, R., Gundersen, T. E., Blomhoff, R., Henderson, C., Wolf, C. R., & Tickle, C.
- Affiliations
- University of Dundee (GB)
- Cancer Research UK (GB)
- Division of Applied Medicine, IMS Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom
- Roslin Institute (GB)
- University of Oslo (NO)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-05-01
- Volume
- 29
- Issue
- 10
- Pages
- 2716-2729
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2682028
- OpenAlex
- W2111707923
- Cited by
- 61
- References
- 100
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 3 · 2012: 4
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Wellcome Trust (072523)
- Cancer Research UK (C4639, C4639/A5661, A5661)
- Royal Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- cytochrome P450 oxidoreductase, cholesterol biosynthesis, limb bud mesenchyme, skeletal development, Antley-Bixler syndrome, limb shortening, syndactyly, retinoic acid metabolism, arachidonic acid metabolism, conditional knockout mice, teratogenesis
- MeSH terms
- Animals, Bone and Bones, Cholesterol, Embryo, Mammalian, Extremities, Humans, Mice, Inbred C57BL, NADPH-Ferrihemoprotein Reductase, Phenotype, Signal Transduction, Limb Deformities, Congenital, Mice, Knockout, Chondrogenesis, Oligonucleotide Array Sequence Analysis, Mice, Antley-Bixler Syndrome Phenotype
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