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J. Biol. Chem., Vol. 279, Issue 18, 18415-18424, April 30, 2004
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Rapid Hepatic Metabolism of 7-Ketocholesterol by 11
-Hydroxysteroid Dehydrogenase Type 1
SPECIES-SPECIFIC DIFFERENCES BETWEEN THE RAT, HUMAN, AND HAMSTER ENZYME*
From the Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, 3010 Berne, Switzerland
The role of 11
-hydroxysteroid dehydrogenase type 1 (11-HSD1) in the local activation of the glucocorticoid receptor by converting inactive 11-ketoglucocorticoids to active 11-hydroxyglucocorticoids is well established. Currently, 11-HSD1 is considered a promising target for treatment of obese and diabetic patients. Here, we demonstrate a role of 11-HSD1 in the metabolism of 7-ketocholesterol (7KC), the major dietary oxysterol. Comparison of recombinant 11-HSD1, transiently expressed in human embryonic kidney 293 cells, revealed the stereo-specific interconversion of 7KC and 7-hydroxycholesterol by rat and human 11-HSD1, whereas the hamster enzyme interconverted 7
-hydroxycholesterol, 7-hydroxycholesterol, and 7KC. In contrast to lysates, which efficiently catalyzed both oxidation and reduction, intact cells exclusively reduced 7KC. These findings were confirmed using rat and hamster liver homogenates, intact rat hepatocytes, and intact hamster liver tissue slices. Reduction of 7KC was abolished upon inhibition of 11-HSD1 by carbenoxolone (CBX) or 2'-hydroxyflavanone. In vivo, after gavage feeding rats, 7KC rapidly appeared in the liver and was converted to 7-hydroxycholesterol. CBX significantly decreased the ratio of 7-hydroxycholesterol to 7KC, supporting the evidence from cell culture experiments for 11-HSD1-dependent reduction of 7KC to 7-hydroxycholesterol. Upon inhibition of 11-HSD1 by CBX, 7KC tended to accumulate in the liver, and plasma 7KC concentration increased. Together, our results suggest that 11-HSD1 efficiently catalyzes the first step in the rapid hepatic metabolism of dietary 7KC, which may explain why dietary 7KC has little or no effect on the development of atherosclerosis.
Received for publication, December 12, 2003 , and in revised form, February 11, 2004.
* This work was supported by Swiss National Science Foundation Grants 3100AO-100060 and NRP50-4050-066575. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
A Cloëtta Research Fellow. To whom correspondence should be addressed: Div. of Nephrology and Hypertension, Dept. of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland. Tel.: 41-31-632-9438; Fax: 41-31-632-9444; E-mail: alex.odermatt{at}dkf2.unibe.ch.
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