Physiological Dissection of the Mevalonate Pathway

项目摘要 他汀类药物是唯一一种持续显示可降低心血管疾病死亡风险的降脂药物， 疾病作为单一疗法。目前，据估计，美国有超过3920万成年人 他汀类药物，新的可能会进一步增加用户数量仅在美国5600万。这突出表明 了解他汀类药物反应性和不良事件的遗传基础的重要性。他汀 主要作用于肝脏，抑制3-羟基-3-甲基戊二酰辅酶A还原酶（Hmgcr）， 甲羟戊酸途径中的酶。除了胆固醇，甲羟戊酸途径还产生其他胆固醇。 必需分子包括：异戊烯基tRNA、血红素A、泛醌、多萜醇、法尼基化和 香叶基香叶基化蛋白质和维生素K2。尽管经过三十多年的研究、开发和临床试验， 根据他汀类药物的经验，许多关于他汀类药物的生理作用和调节的未回答的问题仍然存在。 肝脏中的甲羟戊酸途径。关键的知识差距包括：1）哪些非固醇代谢物是最重要的 对消耗敏感，2）不同甲羟戊酸衍生代谢物对肝细胞功能的必要性， 3)非固醇调节分子的精确身份，4）决定个体差异的遗传因素， LDL-C降低，和5）他汀类药物增加II型糖尿病风险的机制。我们的长期目标 了解控制甲羟戊酸途径和他汀类药物反应的生理机制， 以实现个性化医疗并确定新的药物靶点。我们提出三个具体目标：1）定义 体内肝细胞活力需要哪些类异戊二烯产物，2）测试长萜醇的损失 在有效的Hmgcr抑制期间负责ER应激诱导的细胞凋亡，3）确定Hmgcr的生理学作用。 他汀类药物对体内人肝细胞的影响。成功完成这些研究将确定基本的 肝脏中的甲羟戊酸衍生代谢物，并提高我们对新基因和途径的理解 潜在的他汀类药物相关肝毒性和他汀类药物反应性。

PROJECT SUMMARY Statins are the only lipid lowering agents consistently shown to reduce the risk of death from cardiovascular disease as a monotherapy. Currently, it is estimated that greater than 39.2 million adults in the United States are on statins, and new may further increase the number of users in the U.S. alone to 56.0 million. This underscores the importance of understanding the genetic basis of statin responsiveness as well as adverse events. Statins act primarily in the liver by inhibiting 3-hydroxy-3-methylglutaryl Coenzyme A reductase (Hmgcr), the rate-limiting enzyme in the mevalonate pathway. In addition to cholesterol, the mevalonate pathway also produces other essential molecules including: isopentenyl tRNA, heme A, ubiquinone, dolichol, farnesylated and geranylgeranylated proteins, and vitamin K2. Despite over three decades of research, development, and clinical experience with statins, many unanswered questions remain about the physiological role and regulation of the mevalonate pathway in the liver. Critical gaps in knowledge include: 1) which nonsterol metabolites are most sensitive to depletion, 2) the necessity of the different mevalonate-derived metabolites for hepatocyte function, 3) the precise identity of nonsterol regulatory molecules, 4) genetic factors that determine individual variation in LDL-C lowering, and 5) the mechanisms by which statins increase the risk of type II diabetes. Our long-term goal is understand the physiological mechanisms controlling the mevalonate pathway and statin responsiveness, in order to enable personalized medicine and identify new drug targets. We propose three Specific Aims: 1) Define which isoprenoid products are required for hepatocyte viability in vivo, 2) Test the hypothesis that loss of dolichol is responsible for ER stress-induced apoptosis during potent Hmgcr inhibition, 3) Determine the physiological effects of statins on human hepatocytes in vivo. Successful completion of these studies will define the essential mevalonate-derived metabolites in the liver, and improve our understanding of new genes and pathways underlying statin-related hepatotoxicity and statin responsiveness.