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: 7919405
• 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/7919405
• 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(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(T1 DM，T2 DM)患者的主要死亡原因。动脉粥样硬化是由于富含胆固醇的载脂蛋白B(ApoB)滞留在血管壁内而引起的。重要的是，糖尿病患者有一个独特的、通常被忽视的心血管风险方面的问题，那就是每餐后血浆中肠道来源的载脂蛋白B-脂蛋白(apoB-lib)的显著持久性。原因是肝脏对这些有害颗粒物的清除存在缺陷。这一领域的一个主要障碍是我们对肝脏残留物吸收途径的无知。四分之一世纪前，肝脏对残留物的摄取被证明是独立于低密度脂蛋白受体的。这一认识引发了一场漫长而艰难的寻找责任分子的过程。在1991-1992年间，我们实验室的开创性工作表明，硫酸乙酰肝素蛋白多糖(HSPGs)与残余脂蛋白摄取有关。每个HSPG分子都由一条蛋白质链组成，细胞在蛋白质链上组装被称为硫酸乙酰肝素的糖聚合物，我们证明这种聚合物可以捕获脂蛋白。尽管存在大约50个直接参与肝脏HSPG组装和拆解的基因，但到目前为止，我们的结果表明，在糖尿病中只有两个基因调控失调。此外，T1 DM和T2 DM会引起不同的分子排列紊乱。首先，我们发现NDST1是硫酸乙酰肝素组装过程中的一个关键酶，在体内的T1 DM肝脏中被特异性抑制。第二，在最近的一项重大突破中，我们发现T2 DM在肝脏中诱导了一种新的HSPG降解酶。因此，我们的中心假设是，T1 DM和T2 DM的动脉粥样硬化、餐后血脂异常都是由数量惊人的、直接影响肝脏HSPG结构的关键分子的失调引起的。目的1将利用特异性基因转移来验证NDST1抑制导致T1 DM残留清除受损的假说。由于NDST1缺陷可以掩盖其他HSPG装配酶的缺陷，我们将对未转NDST1和有转NDST1基因的T1 DM的肝脏HSPG的结构、分子生物学以及体内作为残留受体的功能进行深入的研究。目的2将在体内使用特定的基因敲除来验证过表达的降解酶损害T2 DM残留清除的假说。为了确保全面的调查，我们将对T2 DM患者的肝脏HSPG的超微结构、分子生物学和餐后血脂异常进行特征分析，包括无基因敲除和有基因敲除。总体而言，这些拟议的目标将定义HSPG组装中的结构和分子错位，这些错位是导致糖尿病餐后血脂异常的原因。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。 与公共卫生相关：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，部分原因是他们每餐后血浆中有害的肠源性脂蛋白(称为残留物)惊人地持续存在。基于我们的开创性工作暗示了硫酸乙酰肝素蛋白多糖(HSPGs)在肝脏快速、健康地处置残余脂蛋白中的关键作用，我们现在试图表征导致T1 DM和T2 DM肝脏HSPG功能受损的结构和分子紊乱。通过扩大我们对糖尿病餐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心血管疾病带来的巨大负担。