Regulation of Hepatic P450s by Anti-Cholesterol Drugs

心血管疾病，包括冠状动脉疾病和中风，是导致死亡的主要原因。 美国的发病率和死亡率。低密度脂蛋白胆固醇水平升高是一个主要的危险因素， 冠状动脉疾病，超过30%的美国成年人和7%的青少年有高LDL 胆固醇水平。血液胆固醇水平与死亡率之间存在对数线性关系， 冠状动脉疾病，这表明无论起始水平如何，降低胆固醇都是有益的。 肝脏在胆固醇代谢中起主导作用，因此许多药理学方法来降低胆固醇。 胆固醇的目标是肝脏。他汀类药物已被证明有效降低胆固醇水平和死亡率， 冠状动脉疾病，因此它们是美国最广泛使用的药物之一。 然而，他汀类药物也会产生不良反应，并发生药物相互作用。我们的目标是了解 他汀类药物和其他干扰胆固醇代谢的药物的机制谱 调节肝脏过程。这个项目的重点是胆固醇合成的非治疗性后果 抑制，涉及与组成型雄烷受体（CAR）的相互作用， 药物、葡萄糖和脂质代谢的调节剂。这种相互作用在啮齿动物肝细胞中不发生， 强调需要研究人类肝脏系统中的过程。这个项目的假设是， 胆固醇生物合成的抑制抑制人中CAR活化和靶基因表达 这种作用是通过CAR和固醇之间的抑制性相互作用介导的 调节元件结合因子2（SREBP 2）。具体目标是（1）确定胆固醇的影响 在体外和体内对人肝细胞中CAR靶基因表达的合成抑制和（2）定义CAR靶基因表达的抑制。 胆固醇合成抑制调节人肝细胞CAR靶基因表达的机制 细胞为了研究胆固醇合成抑制对CAR调节基因表达的影响， 与人类直接相关的方式，该研究强调使用人类肝细胞， 原代培养和小鼠模型。机械论研究考虑了不同人的复杂性， CAR亚型;评价胆固醇合成抑制对CAR表达、活化和表达的影响。 募集到靶基因的启动子;以及确定CAR和 SREBP 2可能是胆固醇合成抑制对CAR活性影响的基础。这项研究的结果 将为抑制胆固醇生物合成的药物的基本机制提供新的见解 可以影响人类肝细胞生理学的方式，改变异生物质敏感受体敏感 流程.由于这些作用源于对药物预期靶点的抑制，因此它们不容易被抑制。 与药物的治疗效果无关这种影响可能与理解相互之间的关系有关。 代谢的个体差异以及药物不良反应的来源。

Cardiovascular diseases, which include coronary artery disease and stroke, are the leading causes of morbidity and mortality in the United States. Elevated levels of LDL cholesterol are a major risk factor for coronary artery disease, and more than 30% of American adults and 7% of adolescents have high LDL cholesterol levels. There is a log-linear relationship between blood cholesterol level and mortality due to coronary artery disease, which indicates the benefit of cholesterol reduction regardless of the starting level. The liver plays a dominant role in cholesterol metabolism, so many pharmacological approaches to lower cholesterol target the liver. The “statins” have proven effective at reducing cholesterol levels and mortality due to coronary artery disease, and they are therefore among the most widely used drugs in the United States. However, statins also produce adverse effects and undergo drug-drug interactions. Our goal is to understand the spectrum of mechanisms by which statins and other drugs that interfere with cholesterol metabolism regulate hepatic processes. This project focuses on a non-therapeutic consequence of cholesterol synthesis inhibition that involves an interaction with the constitutive androstane receptor (CAR), a xenobiotic-sensing regulator of drug, glucose, and lipid metabolism. This interaction does not occur in rodent hepatocytes, emphasizing the need to study the process in human hepatic systems. The hypothesis of this project is that inhibition of cholesterol biosynthesis suppresses CAR activation and target gene expression in human hepatocytes and that this effect is mediated through an inhibitory interaction between CAR and sterol regulatory element binding factor 2 (SREBP2). The specific aims are to (1) define the impact of cholesterol synthesis inhibition on CAR target gene expression in human hepatocytes in vitro and in vivo and (2) define the mechanism by which cholesterol synthesis inhibition regulates CAR target gene expression in human hepatic cells. To investigate the impact of cholesterol synthesis inhibition on CAR-regulated gene expression in a manner that is directly relevant to humans, the study emphasizes the use of human hepatocytes, both in primary culture and in a mouse model. The mechanistic studies consider the complexity of different human CAR isoforms; evaluate the impact of cholesterol synthesis inhibition on CAR expression, activation, and recruitment to the promoters of target genes; and feature determining how an interaction between CAR and SREBP2 could underlie the impact of cholesterol synthesis inhibition on CAR activity. The findings of this study will provide new insight into the fundamental mechanisms by which drugs that inhibit cholesterol biosynthesis can affect human hepatocellular physiology in a manner that alters xenobiotic-sensing receptor-sensitive processes. Because these effects emanate from inhibition of the drug's intended target, they are not easily dissociated from the drug's therapeutic effects. Such effects are potentially relevant to understanding inter- individual differences in metabolism as well as the origin of adverse drug effects.