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Cholesterol Metabolism

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Cholesterol Metabolism : the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb. / Schmidt, Katy; Hughes, Catherine; Chudek, J. A.; Goodyear, Simon R.; Aspden, Richard M.; Talbot, Richard; Gundersen, Thomas E.; Blomhoff, Rune; Henderson, Colin; Wolf, C. Roland; Tickle, Cheryll.

In: Molecular and Cellular Biology, Vol. 29, No. 10, 15.05.2009, p. 2716-2729.

Research output: Contribution to journalArticle

Harvard

Schmidt, K, Hughes, C, Chudek, JA, Goodyear, SR, Aspden, RM, Talbot, R, Gundersen, TE, Blomhoff, R, Henderson, C, Wolf, CR & Tickle, C 2009, 'Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb' Molecular and Cellular Biology, vol 29, no. 10, pp. 2716-2729., 10.1128/MCB.01638-08

APA

Schmidt, K., Hughes, C., Chudek, J. A., Goodyear, S. R., Aspden, R. M., Talbot, R., ... Tickle, C. (2009). Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb. Molecular and Cellular Biology, 29(10), 2716-2729. 10.1128/MCB.01638-08

Vancouver

Schmidt K, Hughes C, Chudek JA, Goodyear SR, Aspden RM, Talbot R et al. Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb. Molecular and Cellular Biology. 2009 May 15;29(10):2716-2729. Available from: 10.1128/MCB.01638-08

Author

Schmidt, Katy; Hughes, Catherine; Chudek, J. A.; Goodyear, Simon R.; Aspden, Richard M.; Talbot, Richard; Gundersen, Thomas E.; Blomhoff, Rune; Henderson, Colin; Wolf, C. Roland; Tickle, Cheryll / Cholesterol Metabolism : the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb.

In: Molecular and Cellular Biology, Vol. 29, No. 10, 15.05.2009, p. 2716-2729.

Research output: Contribution to journalArticle

Bibtex - Download

@article{e1bdc940d71e4e818418c1a60935409d,
title = "Cholesterol Metabolism: the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb",
keywords = "RETINOIC ACID SYNTHESIS, ANTLEY-BIXLER-SYNDROME, DEVELOPING MOUSE LIMB, LEMLI-OPITZ-SYNDROME, INDIAN HEDGEHOG, ARACHIDONATE METABOLITES, EMBRYONIC-DEVELOPMENT, P450 OXIDOREDUCTASE, FETAL-DEVELOPMENT, BONE-DEVELOPMENT",
author = "Katy Schmidt and Catherine Hughes and Chudek, {J. A.} and Goodyear, {Simon R.} and Aspden, {Richard M.} and Richard Talbot and Gundersen, {Thomas E.} and Rune Blomhoff and Colin Henderson and Wolf, {C. Roland} and Cheryll Tickle",
year = "2009",
doi = "10.1128/MCB.01638-08",
volume = "29",
number = "10",
pages = "2716--2729",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Cholesterol Metabolism

T2 - the Main Pathway Acting Downstream of Cytochrome P450 Oxidoreductase in Skeletal Development of the Limb

A1 - Schmidt,Katy

A1 - Hughes,Catherine

A1 - Chudek,J. A.

A1 - Goodyear,Simon R.

A1 - Aspden,Richard M.

A1 - Talbot,Richard

A1 - Gundersen,Thomas E.

A1 - Blomhoff,Rune

A1 - Henderson,Colin

A1 - Wolf,C. Roland

A1 - Tickle,Cheryll

AU - Schmidt,Katy

AU - Hughes,Catherine

AU - Chudek,J. A.

AU - Goodyear,Simon R.

AU - Aspden,Richard M.

AU - Talbot,Richard

AU - Gundersen,Thomas E.

AU - Blomhoff,Rune

AU - Henderson,Colin

AU - Wolf,C. Roland

AU - Tickle,Cheryll

PY - 2009/5/15

Y1 - 2009/5/15

N2 - <p>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.</p>

AB - <p>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.</p>

KW - RETINOIC ACID SYNTHESIS

KW - ANTLEY-BIXLER-SYNDROME

KW - DEVELOPING MOUSE LIMB

KW - LEMLI-OPITZ-SYNDROME

KW - INDIAN HEDGEHOG

KW - ARACHIDONATE METABOLITES

KW - EMBRYONIC-DEVELOPMENT

KW - P450 OXIDOREDUCTASE

KW - FETAL-DEVELOPMENT

KW - BONE-DEVELOPMENT

U2 - 10.1128/MCB.01638-08

DO - 10.1128/MCB.01638-08

M1 - Article

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 10

VL - 29

SP - 2716

EP - 2729

ER -

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