Divisions of Clinical Chemistry and Clinical Research Center, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Huddinge, Sweden.
J Intern Med. 2011 Oct;270(4):377-87. doi: 10.1111/j.1365-2796.2011.02389.x. Epub 2011 May 9.
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.
To explore the regulatory importance of 24S-OHC in vivo.
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.
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.
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.
氧化固醇如 24S-羟胆固醇（OHC）和 27-羟胆固醇是胆固醇排泄途径的中间产物。此外，它们是肝 X 受体（LXR）类核激素受体的假定内源性激动剂，被认为是胆固醇依赖性基因调控的重要介质。24S-OHC 是已知最有效的内源性 LXR 激动剂之一，存在于大脑和循环中，水平相对较高。
探索 24S-OHC 在体内的调节重要性。
我们开发了一种转基因小鼠模型，其中人类胆固醇 24-羟化酶，负责形成 24S-OHC 的酶，在源自β-肌动蛋白基因的启动子的控制下表达。
雄性和雌性转基因小鼠的大脑、血浆、胆汁和粪便中的 24S-OHC 水平均升高。根据粪便排泄结果，24S-OHC 的产生增加了四到七倍。基因表达谱分析表明，24S-OHC 的产生增加并没有导致预期的大脑或肝脏中 LXR 靶基因的激活。
尽管 24S-OHC 在体外是 LXR 的高效激动剂，但在体内，无论是在大脑还是肝脏，它都不是该核受体靶基因的关键激活剂。
