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 动脉粥样硬化心血管疾病仍然是1型患者的主要死亡原因 和2型糖尿病（T1DM，T2DM）。动脉粥样硬化是由于保留 富含胆固醇，载脂蛋白-B（APOB）在血管壁内含有脂蛋白。重要的是， 糖尿病患者患有独特且通常被忽视的心血管风险方面 在其等离子体中，无肠衍生的apob脂蛋白的惊人持久性被称为“残余” 每顿饭后。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残留摄入途径的无知 进入肝脏。四分之一世纪前，肝脏的残留物被证明与 LDL受体。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与硫酸乙酰肝素蛋白聚糖（HSPG）有关 残留脂蛋白摄取。每个HSPG分子都由蛋白质链组成 我们表现​​出的称为硫酸乙酰肝素的糖聚合物可以捕获脂蛋白。 尽管存在大约50个直接参与肝HSPG组装的基因 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， 硫酸乙酰肝素组件中的键酶，如体内T1DM肝脏中受到特异性抑制。第二， 在最近的主要突破中，我们发现T2DM诱导了一种新型的HSPG降解酶 在肝脏中。因此，我们的中心假设是 T1DM和T2DM均来自少数密钥的失调不足 直接影响肝HSPG结构的分子。 AIM 1将使用特定基因转移到 测试假设NDST1抑制是导致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 hensenthy hensem hensther的肝HSPG结构，分子生物学，并作为残留物的功能 TOR在T1DM中的体内，无NDST1基因转移。 AIM 2将使用特定的敲门 体内测试过表达的降解酶会损害残余清除的假设 在T2DM中。为了确保全面的调查，我们将表征肝HSPG精细结构， T2DM中的分子生物学和餐后血脂异常，没有敲门。 总体而言，这些提出的目标将定义HSPG中的结构和分子扰动 负责糖尿病后餐后血脂异常的组装。工作将扩大我们的 了解糖尿病中过量的心血管疾病，并提供新的治疗靶标。

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