Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function
- Udo Seedorf,
- Martin Raabe,
- Peter Ellinghaus,
- Frank Kannenberg,
- Manfred Fobker,
- Thomas Engel,
- Simone Denis,
- Fred Wouters,
- Karel W.A. Wirtz,
- Ronald J.A. Wanders,
- Nobuyo Maeda, and
- Gerd Assmann
- Institute for Arteriosclerosis Research and Institute for Clinical Chemistry and Laboratory Medicine (Zentrallaboratorium), Westfalian Wilhelms-University, D-48129 Münster, Germany; Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Center for Biomembranes and Lipid Enzymology, University of Utrecht, De Uithof, Utrecht, The Netherlands; Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7525 USA
Abstract
Gene targeting in mice was used to investigate the unknown function of Scp2, encoding sterol carrier protein-2 (SCP2; a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx; a fusion protein between SCP2 and a peroxisomal thiolase). Complete deficiency of SCP2 and SCPx was associated with marked alterations in gene expression, peroxisome proliferation, hypolipidemia, impaired body weight control, and neuropathy. Along with these abnormalities, catabolism of methyl-branched fatty acyl CoAs was impaired. The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(−/−) mice. Further characterization supported that the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA. These results corresponded to high-affinity binding of phytanoyl-CoA to the recombinant rat SCP2 protein, as well as high 3-ketopristanoyl-CoA thiolase activity of the recombinant rat SCPx protein.
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Footnotes
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↵Corresponding author.
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↵This study contains part of a thesis work performed in partial fulfillment of the requirements of the Westfalian Wilhelms-University, Münster, Germany.
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E-MAIL seedorf{at}ear002.uni-muenster.de; FAX 49-251-8356208.
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- Received December 10, 1997.
- Accepted February 9, 1998.
- Cold Spring Harbor Laboratory Press
