Wang Yongjun, Rogers Pamela M, Su Chen, Varga Gabor, Stayrook Keith R, Burris Thomas P
Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA.
J Biol Chem. 2008 Sep 26;283(39):26332-9. doi: 10.1074/jbc.M804808200. Epub 2008 Aug 1.
Cholesterol is required for normal cellular and physiological function, yet dysregulation of cholesterol metabolism is associated with diseases such as atherosclerosis. Cholesterol biosynthesis is regulated by end product negative feedback inhibition where the levels of sterols and oxysterols regulate the expression of cholesterologenic enzymes. Sterol regulatory element-binding protein-2 is responsive to both sterols and oxysterols and has been shown to mediate the transcriptional response of the cholesterologenic enzymes to these lipids. Here, we show that the nuclear hormone receptor for oxysterols, the liver X receptor alpha (LXRalpha), regulates cholesterol biosynthesis by directly silencing the expression of two key cholesterologenic enzymes (lanosterol 14alpha-demethylase (CYP51A1), and squalene synthase (farnesyl diphosphate farnesyl transferase 1)) via novel negative LXR DNA response elements (nLXREs) located in each of these genes. Examination of the CYP51A1 gene revealed that both the SRE and nLXRE are required for normal oxysterol-dependent repression of this gene. Thus, these data suggest that LXRalpha plays an important role in the regulation of cholesterol biosynthesis.
胆固醇是正常细胞和生理功能所必需的，但胆固醇代谢失调与动脉粥样硬化等疾病相关。胆固醇生物合成受终产物负反馈抑制调节，其中固醇和氧化固醇的水平调节胆固醇生成酶的表达。固醇调节元件结合蛋白-2对固醇和氧化固醇均有反应，并已证明可介导胆固醇生成酶对这些脂质的转录反应。在此，我们表明氧化固醇的核激素受体，即肝脏X受体α（LXRα），通过位于这些基因各自中的新型负性LXR DNA反应元件（nLXREs）直接沉默两种关键胆固醇生成酶（羊毛甾醇14α-脱甲基酶（CYP51A1）和鲨烯合酶（法尼基二磷酸法尼基转移酶1））的表达来调节胆固醇生物合成。对CYP51A1基因的研究表明，固醇反应元件（SRE）和nLXRE都是该基因正常的氧化固醇依赖性抑制所必需的。因此，这些数据表明LXRα在胆固醇生物合成的调节中起重要作用。
