HSPGs as remnant receptors: critical role in diabetic postprandial dyslipidemia

HSPG 作为残余受体：在糖尿病餐后血脂异常中发挥关键作用

• 批准号: 7729570
• 负责人: Kevin Jon Williams
• 金额: $ 37.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729570
• 关键词: Affect; Anabolism; Animals; Apolipoproteins B; Area; Atherosclerosis; Binding; Biology; Carbohydrates; Cardiovascular Diseases; Catabolism; Cause of Death; Cell surface; Cells; Cholesterol; Chylomicrons; Core Protein; Data; Deacetylase; Defect; Dependovirus; Diabetes Mellitus; Dyslipidemias; Employee Strikes; Ensure; Enzymes; Evaluation; Exhibits; Functional disorder; Gene Transfer; Genes; Glucosamine; Goals; Growth Factor; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatic; Hepatocyte; Homologous Gene; Human; Hypertriglyceridemia; Inorganic Sulfates; Insulin-Dependent Diabetes Mellitus; Intestines; Knock-out; Laboratories; Ligand Binding Domain; Lipoproteins; Literature; Liver; Liver Circulation; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Masks; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Molecular Biology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathway interactions; Patients; Peripheral; Plasma; Platelet Factor 4; Polymers; Proteins; Proteoglycan; Public Health; Published Comment; Publishing; Role; Seminal; Signal Transduction; Streptozocin; Structure; Surveys; Syndrome; Testing; Tissues; Triglycerides; Unspecified or Sulfate Ion Sulfates; Work; apolipoprotein B receptor; apolipoprotein B-48; base; cardiovascular risk factor; db/db mouse; diabetic; diabetic patient; epimerization; in vivo; insight; knock-down; morphogens; neglect; new therapeutic target; non-diabetic; novel; overexpression; particle; polypeptide; protein expression; public health relevance; receptor; sugar; sulfation; sulfotransferase; type I and type II diabetes; type I diabetic; uptake

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease remains the major cause of death in patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM). Atherosclerosis arises from the retention of cholesterol-rich, apolipoprotein-B (apoB)-containing lipoproteins within the vessel wall. Importantly, diabetic patients suffer from a unique and typically neglected aspect of cardiovascular risk, namely, the striking persistence of intestinally derived apoB-lipoproteins, called 'remnants,' in their plasma after each meal. The cause is a defect in hepatic clearance of these harmful particles. A major impediment in this area has been our ignorance regarding pathways for remnant uptake into liver. Over a quarter century ago, hepatic uptake of remnants was shown to be independent of LDL receptors. This realization launched a long, difficult search for the responsible molecules. In 1991-1992, seminal work from our laboratory implicated heparan sulfate proteoglycans (HSPGs) in remnant lipoprotein uptake. Each HSPG molecule consists of a protein strand onto which the cell assembles sugar polymers, called heparan sulfate, that we showed could capture lipoproteins. Despite the existence of roughly 50 genes that are directly involved in hepatic HSPG assembly and disassembly, our results so far indicate dysregulation of only two of them in diabetes. Moreover, T1DM and T2DM induce distinct molecular derangements. First, we identified Ndst1, a key enzyme in heparan sulfate assembly, as specifically suppressed in T1DM liver in vivo. Second, in a major, recent breakthrough, we found that T2DM induces a novel HSPG degradative enzyme in liver. Thus, our central hypothesis is that the atherogenic, postprandial dyslipidemias of T1DM and T2DM each arise from dysregulation of a surprisingly small number of key molecules that directly affect hepatic HSPG structure. Aim 1 will use specific gene transfer to test the hypothesis that Ndst1 suppression is responsible for impaired remnant clearance in T1DM. Because Ndst1 deficiency can mask defects in other HSPG assembly enzymes, we will compre- hensively characterize hepatic HSPG structure, molecular biology, and function as remnant recep- tors in vivo in T1DM, without and with Ndst1 gene transfer. Aim 2 will use a specific knock-down in vivo to test the hypothesis that the overexpressed degradative enzyme impairs remnant clearance in T2DM. To ensure a comprehensive survey, we will characterize hepatic HSPG fine structure, molecular biology, and postprandial dyslipidemia in T2DM, without and with the knock-down. Overall, these proposed Aims will define the structural and molecular derangements in HSPG assembly that are responsible for diabetic postprandial dyslipidemias. The work will expand our understanding of excess cardiovascular disease in diabetes and provide novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Project relevance to public health Patients with type 1 and type 2 diabetes mellitus suffer from fatal and disabling atherosclerotic cardiovascular disease that results in part from the striking persistence of harmful intestinally derived lipoproteins, called 'remnants,' in their plasma after each meal. Based on our seminal work implicating a crucial role for heparan sulfate proteoglycans (HSPGs) in the rapid, healthy disposal of remnant lipoproteins by the liver, we now seek to characterize the structural and molecular derangements responsible for impaired hepatic HSPG function in T1DM and T2DM. By expanding our understanding of the pathophysiology of diabetic postprandial dyslipidemias, we may be able to avert the tremendous excess burden of cardiovascular disease in diabetes.

描述（由申请人提供）：动脉粥样硬化心血管疾病仍然是1型和2型糖尿病患者（T1DM，T2DM）患者的主要死亡原因。动脉粥样硬化是由富含胆固醇，载脂蛋白-B（APOB）的含脂蛋白的脂蛋白保留的。重要的是，糖尿病患者患心血管风险的独特且通常被忽视的方面，即每顿饭后血浆中无小的衍生的apob脂蛋白（称为“残余）”的持久性。原因是这些有害颗粒的肝清除率缺陷。这一领域的主要障碍是我们对肝脏摄入肝脏的途径的无知。四分之一世纪前，肝脏对残留物的吸收被证明与LDL受体无关。这种认识引发了对负责人分子的漫长而艰难的搜索。在1991 - 1992年，我们实验室的开创性工作牵涉到硫酸乙酰肝素蛋白聚糖（HSPGS）中的残留脂蛋白摄取。每个HSPG分子都由一个蛋白质链组成，细胞在该蛋白质链中组装出我们显示的糖聚合物（称为硫酸乙酰肝素）可以捕获脂蛋白。尽管存在大约50个基因直接参与肝HSPG组装和拆卸，但到目前为止，我们的结果表明其中两个在糖尿病中仅失调。此外，T1DM和T2DM会引起不同的分子扰动。首先，我们确定了NDST1，这是硫酸乙酰肝素组件中的一种键酶，如体内T1DM肝脏中受到了特异性抑制。其次，在最近的主要突破中，我们发现T2DM在肝脏中诱导了一种新型的HSPG降解酶。因此，我们的中心假设是T1DM和T2DM的动脉粥样硬化，餐后血脂异常。每个均来自直接影响肝HSPG结构的令人惊讶的少量关键分子的失调。 AIM 1将使用特定的基因转移来测试NDST1抑制导致T1DM中残留清除受损的假设。由于NDST1缺乏症可以掩盖其他HSPG组装酶中的缺陷，因此我们将综合地表征肝HSPG结构，分子生物学，并在T1DM中，没有NDST1基因转移，在T1DM中充当了Remnant Receptors。 AIM 2将使用特定的敲除体体内来检验以下假设：过表达的降解酶会损害T2DM中残留的清除。为了确保进行全面的调查，我们将表征肝HSPG良好的结构，分子生物学和T2DM中餐后血脂异常，而没有敲门。总体而言，这些提出的目标将定义HSPG组装中负责糖尿病后餐后血脂异常的结构和分子扰动。这项工作将扩大我们对糖尿病中过量心血管疾病的理解，并提供新颖的治疗靶标。 公共卫生相关性：与1型和2型糖尿病的公共卫生患者的项目相关性，梅利氏菌患有致命的和致残的动脉粥样硬化性心血管疾病，部分原因是每顿饭后血浆中有害无性衍生的脂蛋白的惊人持久性，称为“残骸”。基于我们的开创性工作，这意味着肝硫酸盐蛋白聚糖（HSPGS）在肝脏快速，健康处置残留脂蛋白中的至关重要作用，我们现在试图表征导致T1DM和T2DM中肝HSPG功能受损的结构和分子危险。通过扩展我们对糖尿病后血脂异常的病理生理学的理解，我们可能能够避免糖尿病中心血管疾病的巨大负担。