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: 8309295
• 负责人: Kevin Jon Williams
• 金额: $ 37.13万
• 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/8309295
• 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; abstracting; 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; receptor; restoration; sugar; sulfation; sulfotransferase; type I and type II diabetes; type I diabetic; uptake

Project abstract 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.

项目摘要 动脉粥样硬化性心血管疾病仍然是1型糖尿病患者的主要死亡原因 2型糖尿病(T1 DM、T2 DM)。动脉粥样硬化是由于血管内皮细胞 血管壁内富含胆固醇、载脂蛋白B(ApoB)的脂蛋白。重要的是 糖尿病患者患有心血管风险的一个独特且通常被忽视的方面，即， 肠道衍生的载脂蛋白B-脂蛋白在他们的血浆中持续存在的惊人现象 每顿饭后。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残留摄取的途径一无所知 进入肝脏。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。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……里面 1991-1992年，我们实验室的开创性工作表明硫酸乙酰肝素蛋白多糖(HSPGs)在 残余脂蛋白摄取。每个HSPG分子由一条蛋白质链组成，细胞在该链上 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组装的基因 和拆卸，到目前为止，我们的结果表明，在糖尿病患者中，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，我们确定了NDST1，一种 硫酸乙酰肝素组装中的关键酶，在体内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诱导了一种新的HSPG降解酶 在肝脏里。因此，我们的中心假设是导致动脉粥样硬化的餐后血脂异常 T1 DM和T2 DM都是由令人惊讶的少数键的失调引起的 直接影响肝脏HSPG结构的分子。目标1将使用特定的基因转移来 验证NDST1抑制与T1 DM残留物清除受损有关的假设。 由于NDST1缺乏可以掩盖其他HSPG组装酶的缺陷，我们将压缩 对肝脏HSPG的结构、分子生物学和作为残存受体的功能进行了研究。 T1 DM、无NDST1基因转移和有NDST1基因转移的动物体内的TORS。Aim 2将使用特定的击倒在 体内验证过度表达的降解酶损害残留物清除的假设 T2 DM组。为了确保全面的调查，我们将表征肝脏HSPG的精细结构， 分子生物学，以及T2 DM的餐后血脂异常，没有和有基因敲除。 总体而言，这些拟议的目标将定义HSPG的结构和分子错位 负责糖尿病餐后血脂异常的组件。这项工作将扩大我们的 了解糖尿病患者过度的心血管疾病，并提供新的治疗靶点。

项目成果

SULF2 strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus.

• DOI: 10.1002/oby.20682
• 发表时间: 2014-05
• 期刊: OBESITY
• 影响因子: 6.9
• 作者: Hassing, H. Carlijne;Surendran, R. Preethi;Derudas, Bruno;Verrijken, An;Francque, Sven M.;Mooij, Hans L.;Moens, Sophie J. Bernelot;' t Hart, Leen M.;Nijpels, Giel;Dekker, Jacqueline M.;Williams, Kevin Jon;Stroes, Erik S. G.;Van Gaal, Luc F.;Staels, Bart;Nieuwdorp, Max;Dallinga-Thie, Geesje M.
• 通讯作者: Dallinga-Thie, Geesje M.

Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia.

• DOI: 10.1002/hep.25580
• 发表时间: 2012-06
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Hassing, H. Carlijne;Mooij, Hans;Guo, Shuling;Monia, Brett P.;Chen, Keyang;Kulik, Wim;Dallinga-Thie, Geesje M.;Nieuwdorp, Max;Stroes, Erik S. G.;Williams, Kevin Jon
• 通讯作者: Williams, Kevin Jon