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J Lipid Res. 2014 Jun;55(6):1165-72. doi: 10.1194/jlr.P048603. Epub 2014 Apr 25.

On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO.

Author information

1
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
2
Sachs' Children's Hospital, Karolinska Institutet, Stockholm, Sweden.
3
Östersund Hospital, Östersund, Sweden.
4
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN.
5
Department of Clinical Medicine, Faculty of Health Science, University of Tromsö and Division of Cardiothoracic and Respiratory Medicine, University Hospital North Norway, Tromsö, Norway.
6
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
7
Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea, UK.

Abstract

A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP)7A1-catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product. Some patients with cerebrotendinous xanthomatosis (CTX) and all patients with Smith-Lemli-Opitz syndrome (SLO) have markedly increased levels of 7-dehydrocholesterol in plasma and tissues. In addition, the former patients have markedly upregulated CYP7A1. We hypothesized that these patients may produce 7-ketocholesterol from 7-dehydrocholesterol with formation of cholesterol-7,8-epoxide as a side product. In accord with this hypothesis, two patients with CTX were found to have increased levels of 7-ketocholesterol and 7-dehydrocholesterol, as well as a significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Downregulation of CYP7A1 activity by treatment with chenodeoxycholic acid reduced the levels of 7-ketocholesterol in parallel with decreased levels of 7-dehydrocholesterol and cholesterol-7,8-epoxide. Three patients with SLO were found to have markedly elevated levels of 7-ketocholesterol as well as high levels of cholesterol-7,8-epoxide. The results support the hypothesis that 7-dehydrocholesterol is a precursor to 7-ketocholesterol in SLO and some patients with CTX.

KEYWORDS:

Smith-Lemli-Opitz syndrome; cerebrotendinous xanthomatosis; cholesterol 7,8-epoxide; cytochrome P-450 7A1; liquid chromatography-mass spectrometryn

PMID:
24771866
PMCID:
PMC4031947
DOI:
10.1194/jlr.P048603
[Indexed for MEDLINE]
Free PMC Article

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