Enhanced production of 24S-hydroxycholesterol is not sufficient to drive liver X receptor target genes in vivo
Article first published online: 9 MAY 2011
© 2011 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
Volume 270, Issue 4, pages 377–387, October 2011
How to Cite
Shafaati, M., Olin, M., Båvner, A., Pettersson, H., Rozell, B., Meaney, S., Parini, P. and Björkhem, I. (2011), Enhanced production of 24S-hydroxycholesterol is not sufficient to drive liver X receptor target genes in vivo. Journal of Internal Medicine, 270: 377–387. doi: 10.1111/j.1365-2796.2011.02389.x
- Issue published online: 19 SEP 2011
- Article first published online: 9 MAY 2011
- Accepted manuscript online: 12 APR 2011 10:08AM EST
- cholesterol homeostasis;
- LXR agonist;
Abstract. Shafaati M, Olin M, Båvner A, Pettersson H, Rozell B, Meaney S, Parini P, Björkhem I (Karolinska University Hospital Huddinge, Huddinge, Sweden; Dublin Institute of Technology, Dublin, Ireland). Enhanced production of 24S-hydroxycholesterol is not sufficient to drive liver X receptor target genes in vivo. J Intern Med 2011; 270: 377–387.
Background. Oxysterols such as 24S-hydroxycholesterol (OHC) and 27-OHC are intermediates of cholesterol excretion pathways. In addition, they are putative endogenous agonists of the liver X receptor (LXR) class of nuclear hormone receptors and are thought to be important mediators of cholesterol-dependent gene regulation. 24S-OHC is one of the most efficient endogenous LXR agonists known and is present in the brain and in the circulation at relatively high levels.
Objectives. To explore the regulatory importance of 24S-OHC in vivo.
Design. We developed a transgenic mouse model in which human cholesterol 24-hydroxylase, the enzyme responsible for the formation of 24S-OHC, was expressed under the control of a promoter derived from the β-actin gene.
Results. Both male and female transgenic mice had elevated levels of cerebral, plasma, biliary and faecal 24S-OHC. According to the faecal excretion results, production of 24S-OHC was increased four- to sevenfold. Gene expression profiling revealed that the elevated production of 24S-OHC did not result in the anticipated activation of LXR target genes in the brain or liver.
Conclusion. In spite of the fact that 24S-OHC is a highly effective agonist of LXRs in vitro, it is not a critical activator of target genes to this nuclear receptor in vivo, either in the brain or in the liver.