Hepatic PLTP as a target for lowering LDL-c

肝脏 PLTP 作为降低 LDL-c 的目标

• 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
• 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; 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

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）：动脉粥样硬化是全球发病率和死亡率的主要原因。如果目前的糖尿病，肥胖和代谢综合征的流行，如果其管理没有改善，情况将会恶化。他汀类药物的试验为LDL-C降低疗法的好处提供了主要证据，而他汀类药物疗法现在是心血管疾病临床管理的中流。但是，有很多不反应和不宽容的情况。因此，迫切需要采用其他方法来降低血浆LDL-C，最好与他汀类药物协同作用。长期以来，封闭非常低的密度脂蛋白（VLDL）分泌已被认为是替代方案之一。但是，它可能会带来不必要的后果，因为VLDL分泌是一种肝特异性的防御，可防止营养过载或代谢综合征中观察到的过度肝甘油三酸酯积累。因此，靶向VLDL分泌而不引起肝脂质积累是具有挑战性的。 磷脂转移蛋白（PLTP）是降低人血浆LDL-C水平的潜在治疗靶标。我们的早期工作表明，通过降低VLDL分泌的是缺乏肝PLTP，导致PLTP缺乏小鼠的LDL-C水平降低。也许最重要的是，在小鼠的小鼠或高脂肪饮食中，全球PLTP抑制作用不会引起肝脂质的积累。该提案的主要目的是开发一种减少肝PLTP功能的方法，并因此而不会引起肝脂质积累。我们认为，鉴定与PLTP相关的途径和蛋白质具有揭示调节肝PLTP功能的其他途径的潜力。基于初步工作，我们建议表征Furin，Proprotein转化酶家族成员和体内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prof蛋白过度表达（全长脂蛋白的N末端片段）的潜在机制，从而降低了促进VLDL分泌的影响O PLTP。此外，将在小鼠中评估基于prof蛋白的降低等离子体LDL-C水平的策略的治疗潜力。 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LDL-C水平的新策略提供证据，这将有效。