Sulfatase-2: Key mediator of atherogenic postprandial dyslipoproteinemia

Sulfatase-2：致动脉粥样硬化餐后异常脂蛋白血症的关键介质

基本信息

批准号：
8735948
负责人：
Kevin Jon Williams
金额：
$ 39万
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：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8735948
关键词：
Affect Antisense Oligonucleotides Area Arterial Fatty Streak Atherosclerosis Attenuated Binding Biological Assay Biology Breeding Cardiovascular system Catabolism Cell surface Clinical Corn Oil Defect Development Dyslipidemias Employee Strikes Enzymes Event Exhibits Fasting Genes Growth Factor Heparan Sulfate Proteoglycan Heparitin Sulfate Hepatic Hepatocyte Human In Vitro Individual Inorganic Sulfates Insulin Insulin Receptor Insulin Resistance Knockout Mice Laboratories Ligands Link Lipoproteins Liver Low-Density Lipoproteins Mediating Mediator of activation protein Metabolic Methods Modeling Molecular Molecular Chaperones Mus Nature Non-Insulin-Dependent Diabetes Mellitus Participant Patients Plasma Prevalence Protein Biosynthesis Proteins Proto-Oncogene Proteins c-akt Publishing Regulation Research Residual state Role Series Signal Pathway Signal Transduction Sulfatases Syndrome Therapeutic Translations Triglycerides Unspecified or Sulfate Ion Sulfates Work apolipoprotein B-48 base cardiovascular disorder risk cohort dyslipoproteinemia hypercholesterolemia improved in vivo inhibitor/antagonist insulin signaling lipoprotein-remnant receptor macrophage morphogens novel novel strategies overexpression particle protein degradation public health relevance receptor syndecan therapeutic target

项目摘要

The overwhelming majority of patients with type 2 diabetes mellitus (T2DM) and related syndromes die from accelerated atherosclerosis. These patients exhibit a striking persistence of postprandial TG-rich lipoproteins, called ‘remnants,’ in their plasma after each meal. Importantly, remnants have been linked to human cardiovascular events. Because the basis for delayed remnant clearance in T2DM patients has been poorly understood, no therapeutic strategies are available to selectively target these harmful particles. Our laboratory has made a series of fundamental advances in this area. First, we identified the syndecan-1 heparan sulfate proteoglycan (HSPG) as a remnant receptor. Second, using an array, we found dysregulation of exactly one gene that would impair syndecan-1 function in remnant clearance – namely, sulfatase-2 (Sulf2), which is 10-fold overexpressed in T2DM liver. SULF2 impedes syndecan-1-mediated catabolism of remnants by liver cells. Third, we just published that inhibition of hepatic Sulf2 in vivo flattens plasma TG excursions after corn-oil gavage in T2DM mice. Fourth, we discovered that insulin suppresses SULF2 protein posttranscriptionally, and that this effect becomes insulin-resistant in T2DM liver, related to impaired AKT activation. By focusing on SULF2, we will improve our understanding of postprandial dyslipidemia and facilitate the translation of our work into clinical utility. Aim 1: Molecular mechanisms for the normal suppression of sulfatase-2 protein by insulin. Hypothesis 1: Understanding the normal regulation of hepatic SULF2 expression will reveal key nodes that are potential therapeutic targets. Virtually nothing is currently known about how insulin suppresses hepatocyte expression of SULF2. We will investigate SULF2 regulation by working from the insulin receptor and the PI3 kinase-AKT pathway downwards (Aim 1a) and from the SULF2 protein upwards (Aim 1b). Aim 2: Novel strategies to correct hepatic SULF2 overexpression in T2DM db/db liver, and hence attenuate postprandial dyslipoproteinemia. Hypothesis 2: Inhibition of SULF2 is a viable therapeutic strategy, and we will take this concept beyond our previous ASO method. Here, we will manipulate in vivo the novel AKT-dependent participants in SULF2 regulation that we identify in Aim 1. Overall, these proposed Aims will substantially advance our molecular understanding and our abilities to correct the devastating health burden from postprandial dyslipoproteinemia in T2DM.

绝大多数2型糖尿病患者（T2DM）和相关综合症患者死于加速动脉粥样硬化。这些患者在每顿饭后的血浆中表现出餐后富含TG的脂蛋白的持久性，称为“残留物”。重要的是，残留物与人类心血管事件有关。由于T2DM患者的延迟残留清除的基础知之甚少，因此没有治疗策略可有选择地针对这些有害颗粒。我们的实验室在这一领域取得了一系列的基本进步。首先，我们将syndecan-1乙par硫酸盐蛋白聚糖（HSPG）确定为残留受体。其次，使用阵列，我们发现一个基因的失调恰好会损害syndecan-1在残留清除中的功能 - 即硫酸酶-2（Sulf2），该基因在T2DM肝脏中过表达10倍。 SULF2阻碍了肝细胞残留的syndecan-1介导的分解代谢。第三，我们刚刚发表了T2DM小鼠的玉米油饲料后的肝硫酸抑制在体内抑制血浆TG游览。第四，我们发现胰岛素在转录后抑制了Sulf2蛋白，并且这种作用在T2DM肝脏中具有胰岛素耐药性，这与AKT激活受损有关。通过专注于Sulf2，我们将提高对餐后血脂异常的理解，并促进我们的工作转化为临床实用性。 AIM 1：通过胰岛素正常抑制硫酸酶-2蛋白的分子机制。假设1：了解肝Sulf2表达的正常调节将揭示潜在的治疗靶标的关键淋巴结。实际上，目前尚无关于胰岛素如何抑制Sulf2的肝细胞表达。我们将通过从胰岛素受体和PI3激酶-AKT向下（AIM 1A）和向上的Sulf2蛋白（AIM 1B）进行工作（AIM 1B）来研究Sulf2调节。 AIM 2：纠正T2DM DB/DB肝脏中肝硫酸过表达的新型策略，因此减轻了餐后血脂异常血症。假设2：抑制Sulf2是一种可行的治疗策略，我们将把这个概念超出我们以前的ASO方法。在这里，我们将在体内操纵新型Akt依赖于Sulf2调节的参与者，我们在AIM 1中识别。总体而言，这些提出的目标将大大提高我们的分子理解和纠正T2DM中餐后血脂异常血症的毁灭性健康燃烧的能力。