Physiological Dissection of the Mevalonate Pathway

项目总结 他汀类药物是唯一一直被证明可以降低心血管死亡风险的降血脂药物 疾病作为一种单一疗法。目前，据估计，美国有超过3920万成年人是 在他汀类药物方面，NEW可能会进一步将仅在美国的用户数量增加到5600万。这强调了 了解他汀类药物反应性的遗传基础以及不良事件的重要性。他汀类药物 主要通过抑制3-羟基-3-甲基戊二酰辅酶A还原酶(Hmgcr)在肝脏发挥作用，Hmgcr是限速酶 甲氧戊酸途径中的酶。除胆固醇外，甲氧戊酸途径还会产生其他 基本分子包括：异戊烯基tRNA、血红素A、泛醌、二苯二酚、法尼化和 香叶基香叶蛋白和维生素K2。尽管经过了三十多年的研究、开发和临床 关于他汀类药物的经验，关于他汀类药物的生理作用和调节仍有许多悬而未决的问题。 甲氧戊酸在肝脏中的途径。知识方面的关键差距包括：1)哪些非甾醇代谢物最多 对消耗敏感，2)甲氧戊酸衍生的不同代谢物对肝细胞功能的必要性， 3)非固醇调节分子的精确识别，4)决定个体差异的遗传因素。 降低低密度脂蛋白，以及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 了解甲氧丙戊酸途径和他汀类药物反应的生理机制 以实现个性化药物和识别新的药物靶点。我们提出了三个具体目标：1)定义 体内肝细胞存活所需的类异戊二烯产物，2)检验二氢异戊二烯丢失的假设 在内质网应激诱导的细胞凋亡过程中对Hmgcr有很强的抑制作用，3)决定生理性的 他汀类药物对活体人肝细胞的影响。成功完成这些研究将确定必要的 肝脏中甲氧戊酸衍生的代谢物，并提高我们对新基因和途径的理解 潜在的他汀类药物的肝毒性和他汀类药物的反应性。

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.