title: Enhanced production of 24S-hydroxycholesterol is not sufficient to drive liver X receptor target genes in vivo.
abstract: 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.
  
  
  OBJECTIVE
  To explore the regulatory importance of 24S-OHC in vivo.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Divisions of Clinical Chemistry and Clinical Research Center, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Huddinge, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Shafaati
authors.forename: M
authors.initials: M
authors.lastname: Olin
authors.forename: A
authors.initials: A
authors.lastname: Båvner
authors.forename: H
authors.initials: H
authors.lastname: Pettersson
authors.forename: B
authors.initials: B
authors.lastname: Rozell
authors.forename: S
authors.initials: S
authors.lastname: Meaney
authors.forename: P
authors.initials: P
authors.lastname: Parini
authors.forename: I
authors.initials: I
authors.lastname: Björkhem
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D013250:Steroid Hydroxylases / Q000235:genetics
chemical_list: D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C044563:24-hydroxycholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase