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

Ingemar Björkhem, Ulf Diczfalusy, Anita Lövgren-Sandblom, Lena Starck, Monica Jonsson, Keri Tallman, Henrik Schirmer, Lilian Bomme Ousager, Peter J Crick, Yuqin Wang, William J Griffiths, F Peter Guengerich

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftJournal of Lipid Research
Vol/bind55
Udgave nummer6
Sider (fra-til)1165-1172
ISSN0022-2275
DOI
StatusUdgivet - 25. apr. 2014

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