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Journal of Lipid Research, Vol. 45, 81-88, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Regulation of sterol carrier protein gene expression by the Forkhead transcription factor FOXO3a

Tobias B. Dansen^1,3,2,*, Geert J. P. L. Kops^1,4,, Simone Denis, Nannette Jelluma^*, Ronald J. A. Wanders, Johannes L. Bos, Boudewijn M. T. Burgering and Karel W. A. Wirtz^*

^* Department of Biochemistry of Lipids, Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Centre, Heidelberglaan 100, 3584 CG Utrecht, The Netherlands
Departments of Clinical Chemistry and Pediatrics, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

² To whom correspondence should be addressed. e-mail: tdansen{at}cc.ucsf.edu

The SCP gene encodes two proteins, sterol carrier protein X (SCPx) and SCP2, that are independently regulated by separate promoters. SCPx has been shown to be the thiolase involved in the breakdown of branched-chain fatty acids and in the biosynthesis of bile acids. The in vivo function of SCP2 however remains to be established. The transcriptional regulation of SCPx and SCP2 is unclear, but their promoter regions contain several putative regulatory domains. We show here that both SCPx and SCP2 are upregulated by the daf-16-like Forkhead transcription factor FOXO3a (also known as FKHRL1) on the level of promoter activity. It was recently described that Forkheads regulate protection against (oxidative) stress in both Caenorhabditis elegans and mammalian cells. We looked into a role for SCP2 in the cellular defense against oxidative damage and found that a fluorescent fatty acid analog bound to SCP2 is protected against H₂O₂/Cu²⁺-induced oxidative damage.

We propose a model for the way in which SCP2 could protect fatty acids from peroxidation.

Supplementary key words oxidative stress • aging • peroxisome • fatty acid oxidation

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