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.

绝大多数患有 2 型糖尿病 (T2DM) 和相关综合征的患者死于加速动脉粥样硬化，这些患者在每餐后的血浆中表现出惊人的富含甘油三酯的脂蛋白，称为“残余物”。由于对 T2DM 患者残余物清除延迟的基础了解甚少，因此尚无选择性针对这些有害颗粒的治疗策略。我们的实验室在这一领域取得了一系列基础性进展，首先，我们确定了 syndecan-1 硫酸乙酰肝素蛋白聚糖 (HSPG) 作为一种残余受体。 SULF2 在残余物清除中发挥作用，即硫酸酯酶 2 (Sulf2)，SULF2 在 T2DM 肝脏中过度表达 10 倍，阻碍 syndecan-1 介导。第三，我们刚刚发表了在 T2DM 小鼠中，体内抑制肝脏 Sulf2 可以使玉米油灌胃后血浆 TG 漂移变平。第四，我们发现胰岛素在转录后抑制 SULF2 蛋白，并且这种作用变成了胰岛素- T2DM 肝脏中的耐药性与 AKT 激活受损有关通过关注 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。公用事业。目标 1：胰岛素正常抑制硫酸酯酶 2 蛋白的分子机制假设 1：了解肝脏 SULF2 表达的正常调节将揭示潜在治疗靶标的关键，目前对胰岛素如何抑制肝细胞 SULF2 表达几乎一无所知。我们将通过从胰岛素受体和 PI3 激酶-AKT 通路向下（目标 1a）和从 SULF2 蛋白向上研究 SULF2 调节。（目标 1b）。目标 2：纠正 T2DM db/db 肝脏中 SULF2 过度表达的新策略，从而减轻餐后异常脂蛋白血症。假设 2：抑制 SULF2 是一种可行的治疗策略，我们将在之前的 ASO 方法之外采用这一概念。将在体内操纵我们在目标 1 中确定的 SULF2 调节中新型 AKT 依赖性参与者。总体而言，这些提出的目标将大大促进我们的分子理解和纠正 T2DM 餐后异常脂蛋白血症造成的破坏性健康负担的能力。