Hepatic PLTP as a target for lowering LDL-c

肝脏 PLTP 作为降低 LDL-c 的目标

基本信息

批准号：
8916209
负责人：
XIAN-CHENG JIANG
金额：
$ 40万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916209
关键词：
Animals Atherosclerosis Binding Biology Cardiovascular Diseases Chemicals Cholesterol Clinical Management Computer Simulation Diabetes Mellitus Diagnosis Diet Dyslipidemias Engineering Epidemic Family Fatty acid glycerol esters Goals Health Hepatic High Density Lipoproteins Human In Vitro Insulin Investigation LDL Cholesterol Lipoproteins Length Lipids Liver Low-Density Lipoproteins Medical Metabolic syndrome Morbidity - disease rate Mus N-terminal Nutritional Obesity Pathway interactions Phospholipid Transfer Proteins Plasma Polyubiquitination Prevention Proprotein Convertases Protein Inhibition Protein Secretion Proteins Regulation Signal Transduction Testing Therapeutic Triglycerides United States Variant Very low density lipoprotein Work base cardiovascular risk factor in vivo inhibitor/antagonist member mortality multicatalytic endopeptidase complex mutant novel strategies overexpression polypeptide protein complex protein degradation protein function public health relevance research study small molecule therapeutic target

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化是全世界发病和死亡的主要原因。由于目前糖尿病、肥胖症和代谢综合征的流行，如果不改善管理，情况将会恶化。他汀类药物试验为降低 LDL-c 疗法的益处提供了主要证据，他汀类药物疗法现已成为心血管疾病临床管理的支柱。然而，存在许多反应迟钝和不宽容的情况。因此，迫切需要其他方法来降低血浆 LDL-c，优选与他汀类药物协同作用。阻断极低密度脂蛋白（VLDL）分泌长期以来一直被认为是替代方案之一。然而，它可能会产生不良后果，因为 VLDL 分泌是一种肝脏特异性防御机制，可防止营养过剩或代谢综合征中肝脏甘油三酯过度积累。因此，靶向 VLDL 分泌而不引起肝脏脂质积累具有挑战性。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 的缺乏，通过减少 VLDL 分泌，导致 PLTP 缺陷小鼠中 LDL-c 水平降低。也许最重要的是，在吃食物或高脂肪饮食的小鼠中，整体 PLTP 抑制不会导致肝脏脂质积累。该提案的主要目标是开发一种方法，在不引起肝脏脂质积累的情况下降低肝脏 PLTP 功能，从而降低血浆 LDL-c。我们推断，鉴定与 PLTP 相关的途径和蛋白质有可能揭示调控肝 PLTP 功能的其他途径。基于前期工作，我们建议表征前蛋白转化酶家族成员弗林蛋白酶与体内 PLTP 之间的相互作用，并确定其对血浆脂质水平的影响。特别是，我们将研究 Profurin（全长 Furin 的 N 末端片段）过度表达降低 PLTP 促进 VLDL 分泌作用的潜在机制。此外，还将在小鼠中评估基于脯氨酸的策略降低血浆 LDL-c 水平的治疗潜力。我们预计该项目将拓宽我们对 PLTP 和弗林蛋白酶生物学的理解，并为降低血浆 LDL-c 水平的新策略提供证据，该策略对人类有效。