Hepatic PLTP as a target for lowering LDL-c

描述(申请人提供)：动脉粥样硬化是全球发病率和死亡率的主要原因。如果不改善其管理，由于目前糖尿病、肥胖症和代谢综合征的流行，情况将会恶化。他汀类药物试验已经为降低低密度脂蛋白治疗的益处提供了主要证据，他汀类药物治疗现在是心血管疾病临床治疗的主要手段。然而，有许多不响应和不容忍的情况。因此，迫切需要其他方法来降低血浆低密度脂蛋白-c，最好是与他汀类药物协同作用。阻断极低密度脂蛋白(VLDL)的分泌长期以来一直被认为是替代方案之一。然而，它可能会产生不希望看到的后果，因为极低密度脂蛋白的分泌是肝脏特有的防御措施，可以防止在营养过载或代谢综合征中出现的肝脏甘油三酯过度堆积。因此，在不引起肝脏脂质堆积的情况下靶向VLDL的分泌是具有挑战性的。磷脂转移蛋白(PLTP)是降低人类血浆低密度脂蛋白-c水平的潜在治疗靶点。我们的早期工作表明，PLTP缺陷小鼠的低密度脂蛋白水平降低是由于肝脏PLTP的缺乏，通过减少极低密度脂蛋白的分泌来实现的。也许最重要的是，在饮食或高脂饮食的小鼠中，全局抑制PLTP并没有导致肝脏脂肪堆积。这项建议的主要目标是开发一种方法，在不引起肝脏脂质堆积的情况下，降低肝脏PLTP功能，从而降低血浆低密度脂蛋白-c。我们认为，识别与PLTP相关的途径和蛋白有可能揭示调节肝脏PLTP功能的其他途径。在前期工作的基础上，我们建议研究原蛋白转换酶家族成员Furin与PLTP在体内的相互作用，并确定其对血脂水平的影响。特别是，我们将研究过表达proFurin(全长Furin的N端片段)降低PLTP促进VLDL分泌的潜在机制。此外，将在小鼠身上评估以普罗夫林为基础的降低血浆低密度脂蛋白水平的治疗潜力。我们预计该项目将扩大我们对PLTP和Furin生物学的理解，并为降低血浆低密度脂蛋白水平的新策略提供证据，该策略将对人类有效。

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of morbidity and mortality worldwide. The situation will worsen due to the current epidemic of diabetes, obesity and metabolic syndrome if there is no improvement in its management. Statin trials have provided the major evidence for the benefits of an LDL-c lowering therapy and statin therapy is now the mainstay of cardiovascular disease clinical management. However, there are many instances of unresponsiveness and intolerance. There is thus an urgent need for additional approaches to lower plasma LDL-c, preferably acting synergistically with statins. Blocking very low density lipoprotein (VLDL) secretion has long been recognized as one of the alternatives. However, it can have unwanted consequences, because VLDL secretion is a hepatic-specific defense to protect against the excessive liver triglyceride accumulation seen in nutritional overload or metabolic syndrome. Thus targeting VLDL secretion without causing hepatic lipid accumulation is challenging. Phospholipid transfer protein (PLTP) is a potential therapeutic target for lowering plasma LDL-c levels in humans. Our early work indicates that it is the lack of hepatic PLTP, by decreasing VLDL secretion that is responsible for the reduced LDL-c levels in PLTP deficient mice. Perhaps most significantly, in mice on either a chow or high fat diet, global PLTP inhibition did not cause hepatic lipid accumulation. The major goal of this proposal is to develop an approach for the reduction of hepatic PLTP function and hence plasma LDL-c without causing hepatic lipid accumulation. We reasoned that identifying pathways and proteins associated with PLTP had the potential to reveal additional avenues for regulation of hepatic PLTP function. Based on preliminary work, we propose to characterize the interaction between furin, a member of the proprotein convertase family, and PLTP in vivo, and determine its effect on plasma lipid levels. In particular, we will investigate the underlying mechanisms by which overexpression of profurin (the N-terminal fragment of the full-length furin) reduces the effects o PLTP in promoting VLDL secretion. Furthermore, the therapeutic potential of a profurin-based strategy for the lowering of plasma LDL-c levels will be evaluated in mice. We anticipate that this project will broaden our understanding of both PLTP and furin biology and provide evidence for a novel strategy for lowering plasma LDL-c levels that will be effective in humans.