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

基本信息

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
项目类别：
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

项目摘要

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）：动脉粥样硬化性心血管疾病仍然是 1 型和 2 型糖尿病（T1DM、T2DM）患者死亡的主要原因。动脉粥样硬化是由于富含胆固醇、含载脂蛋白 B (apoB) 的脂蛋白滞留在血管壁内而引起的。重要的是，糖尿病患者患有一个独特且通常被忽视的心血管风险，即每餐后血浆中肠道来源的apoB脂蛋白（称为“残留物”）的惊人持续存在。原因是肝脏清除这些有害颗粒的缺陷。该领域的一个主要障碍是我们对肝脏摄取残余物的途径的无知。四分之一个多世纪前，肝脏对残余物的摄取被证明与低密度脂蛋白受体无关。这一认识引发了对负责分子的漫长而艰难的探索。 1991-1992 年，我们实验室的开创性工作表明硫酸乙酰肝素蛋白聚糖 (HSPG) 与残余脂蛋白的摄取有关。每个 HSPG 分子都由一条蛋白质链组成，细胞在该蛋白质链上组装糖聚合物，称为硫酸乙酰肝素，我们证明它可以捕获脂蛋白。尽管存在大约 50 个直接参与肝脏 HSPG 组装和分解的基因，但迄今为止我们的结果表明，糖尿病中只有其中两个基因失调。此外，T1DM 和 T2DM 会引起不同的分子紊乱。首先，我们鉴定了 Ndst1，硫酸乙酰肝素组装中的关键酶，在体内 T1DM 肝脏中被特异性抑制。其次，在最近的一项重大突破中，我们发现 T2DM 在肝脏中诱导一种新型 HSPG 降解酶。因此，我们的中心假设是，T1DM 和 T2DM 的致动脉粥样化、餐后血脂异常均是由直接影响肝脏 HSPG 结构的少数关键分子的失调引起的。目标 1 将使用特定的基因转移来检验 Ndst1 抑制导致 T1DM 残余清除受损的假设。由于 Ndst1 缺陷可以掩盖其他 HSPG 组装酶的缺陷，因此我们将全面表征 T1DM 中肝脏 HSPG 的结构、分子生物学和体内残余受体的功能，无论是否有 Ndst1 基因转移。目标 2 将使用体内特定的敲低来测试过度表达的降解酶会损害 T2DM 中残余物清除的假设。为了确保全面的调查，我们将表征 T2DM 中肝脏 HSPG 的精细结构、分子生物学和餐后血脂异常，无论是否存在敲低。总体而言，这些提出的目标将定义 HSPG 组装中导致糖尿病餐后血脂异常的结构和分子紊乱。这项工作将扩大我们对糖尿病中过度心血管疾病的理解，并提供新的治疗靶点。公共健康相关性：项目与公共健康的相关性 1 型和 2 型糖尿病患者患有致命性和致残性动脉粥样硬化性心血管疾病，其部分原因是每次治疗后血浆中有害的肠源性脂蛋白（称为“残余物”）的惊人持续存在。一顿饭。我们的开创性工作表明硫酸乙酰肝素蛋白聚糖 (HSPG) 在肝脏快速、健康地处理残余脂蛋白中发挥着至关重要的作用，基于此，我们现在试图描述 T1DM 和 T2DM 中导致肝 HSPG 功能受损的结构和分子紊乱的特征。通过扩大我们对糖尿病餐后血脂异常病理生理学的了解，我们也许能够避免糖尿病带来的心血管疾病的巨大负担。