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J Biol Chem, Vol. 274, Issue 50, 35455-35460, December 10, 1999

Aberrant Oxidation of the Cholesterol Side Chain in Bile Acid Synthesis of Sterol Carrier Protein-2/Sterol Carrier Protein-x Knockout Mice^*

Frank Kannenberg, Peter Ellinghaus, Gerd Assmann, and Udo Seedorf

From the Institut für Arterioskleroseforschung and the Institut für Klinische Chemie und Laboratoriumsmedizin (Zentrallaboratorium) der Westfälischen Wilhelms-Universität Münster, D-48129 Münster, Germany

Peroxisomal -oxidation plays an important role in the metabolism of a wide range of substrates, including various fatty acids and the steroid side chain in bile acid synthesis. Two distinct thiolases have been implicated to function in peroxisomal -oxidation: the long known 41-kDa -ketothiolase identified by Hashimoto and co-workers (Hijikata, M., Ishii, N., Kagamiyama, H., Osumi, T., and Hashimoto, T. (1987) J. Biol. Chem. 262, 8151-8158) and the recently discovered 60-kDa SCPx thiolase, that consists of an N-terminal domain with -ketothiolase activity and a C-terminal moiety of sterol carrier protein-2 (SCP2, a lipid carrier or transfer protein). Recently, gene targeting of the SCP2/SCPx gene has shown in mice that the SCPx -ketothiolase is involved in peroxisomal -oxidation of 2-methyl-branched chain fatty acids like pristanic acid. In our present work we have investigated bile acid synthesis in the SCP2/SCPx knockout mice. Specific inhibition of -oxidation at the thiolytic cleavage step in bile acid synthesis is supported by our finding of pronounced accumulation in bile and serum from the knockout mice of 3,7,12-trihydroxy-27-nor-5-cholestane-24-one (which is a known bile alcohol derivative of the cholic acid synthetic intermediate 3,7,12-trihydroxy-24-keto-cholestanoyl-coenzyme A). Moreover, these mice have elevated concentrations of bile acids with shortened side chains (i.e. 23-norcholic acid and 23-norchenodeoxycholic acid), which may be produced via - rather than -oxidation. Our results demonstrate that the SCPx thiolase is critical for -oxidation of the steroid side chain in conversion of cholesterol into bile acids.

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^* This work was supported by Deutsche Forschungsgemeinschaft Grant Se 459/2-3 (to U. S.) and by the Interdisziplinäres Klinisches Forschungszentrum of the Medical Faculty, University of Münster (Project A4).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Institut für Arterioskleroseforschung, Domagkstr. 3, 48149 Münster, Germany. Tel.: 49-251-8356197; Fax: 49-251-8355187; E-mail: seedorfu@uni-muenster.de.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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