Masson David, Staels Bart, Gautier Thomas, Desrumaux Catherine, Athias Anne, Le Guern Naig, Schneider Martina, Zak Zoulika, Dumont Laure, Deckert Valérie, Tall Alan, Jiang Xian-Cheng, Lagrost Laurent
Institut National de la Santé et de la Recherche Médicale U498, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France.
J Lipid Res. 2004 Mar;45(3):543-50. doi: 10.1194/jlr.M300432-JLR200. Epub 2003 Dec 16.
Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of CETPTg mice was reversed by LXR agonist treatment. Moreover, LXR activation induced a 2-fold increase in hepatic LDL-receptor expression in wild-type and CETPTg mice, and it produced a significantly greater rise in biliary cholesterol concentration in CETPTg mice as compared with wild-type mice. In conclusion, induction of CETP constitutes a major determinant of the effect of LXR agonists on cholesterol transport and excretion.
与小鼠血浆不同，人血浆中含有可能影响胆固醇逆向转运的胆固醇酯转运蛋白（CETP）。肝脏X受体（LXR）是一种被氧化甾醇激活的核受体，它通过CETP基因启动子中的直接重复序列4元件诱导CETP转录。本研究的目的是在体内评估LXR激活对CETP表达的影响及其对血浆脂质代谢以及肝脏和胆汁脂质含量的影响。用T0901317 LXR激动剂对表达CETP的野生型和人源化小鼠进行了为期五天的治疗。这种治疗使肝脏CETP mRNA和血浆CETP活性水平均显著升高。有趣的是，在CETP转基因小鼠中未观察到LXR激动剂介导的野生型小鼠总胆固醇和高密度脂蛋白胆固醇水平升高两倍的情况，且LXR激动剂治疗可逆转CETP转基因小鼠肝脏中的胆固醇蓄积。此外，LXR激活使野生型和CETP转基因小鼠肝脏低密度脂蛋白受体表达增加两倍，与野生型小鼠相比，它使CETP转基因小鼠胆汁胆固醇浓度升高更为显著。总之，CETP的诱导是LXR激动剂对胆固醇转运和排泄作用的主要决定因素。
