Enhanced production of 24S‐hydroxycholesterol is not sufficient to drive liver X receptor target genes in vivo

Abstract.  Shafaati M, Olin M, Bavner A, Pettersson H, Rozell B, Meaney S, Parini P, Bjorkhem 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.