Hepatic PLTP as a target for lowering LDL-c

描述（由申请人提供）：动脉粥样硬化是世界范围内发病率和死亡率的主要原因。由于糖尿病、肥胖症和代谢综合征的流行，如果不改善管理，情况将进一步恶化。他汀类药物试验为降低LDL-c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，迫切需要其他降低血浆LDL-c的方法，最好是与他汀类药物协同作用。阻断极低密度脂蛋白（VLDL）的分泌一直被认为是一种替代方法。然而，它可能会产生意想不到的后果，因为VLDL的分泌是一种肝脏特异性防御，以防止营养超载或代谢综合征中肝脏甘油三酯的过度积累。因此，靶向VLDL分泌而不引起肝脏脂质积累是具有挑战性的。磷脂转移蛋白（PLTP）是降低人类血浆LDL-c水平的潜在治疗靶点。我们的早期工作表明，肝脏PLTP缺乏，通过减少VLDL分泌，导致PLTP缺乏小鼠LDL-c水平降低。也许最重要的是，在小鼠中，无论是吃食物还是高脂肪饮食，PLTP的抑制都不会引起肝脏脂质积累。本提案的主要目标是开发一种方法来降低肝脏PLTP功能，从而降低血浆LDL-c，而不引起肝脏脂质积累。我们推断，确定与PLTP相关的途径和蛋白质有可能揭示肝脏PLTP功能调节的其他途径。在前期工作的基础上，我们拟对蛋白转化酶家族成员furin与PLTP在体内的相互作用进行表征，并确定其对血脂水平的影响。特别是，我们将研究profurin（全长furin的n端片段）过表达降低PLTP促进VLDL分泌作用的潜在机制。此外，将在小鼠中评估以丙尿素为基础的降低血浆LDL-c水平的治疗潜力。我们期望这个项目将拓宽我们对PLTP和furin生物学的理解，并为有效降低人类血浆LDL-c水平的新策略提供证据。

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.