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

• 批准号: 8613570
• 负责人: Kevin Jon Williams
• 金额: $ 38.75万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 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/8613570
• 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

DESCRIPTION (provided by applicant): 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 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 owing to a defect in NOX4 function that impairs AKT activation. By focusing on SULF2, we will improve our under- standing of postprandial dyslipidemia and facilitate the translation of our work into clinicl utility. Aim 1: Role of sulfatase-2 in atherosclerosis: lipoprotein and non-lipoprotein effects. Hypothesis 1: Inhibition of SULF2 will slow atherosclerosis through two effects: in the liver by improving the plasma lipoprotein profile and in the arterial wall by impeding local pro-atherogenic signaling pathways, particularly Wnt. We will examine atherosclerotic lesion development in SULF2-deficient mice, bred into major atherosclerosis models. Beneficial effects of SULF2 deficiency will further bolster our therapeutic focus. Aim 2: Molecular mechanisms for overexpression of sulfatase-2 in T2DM liver. Hypothesis 2: Hepatic SULF2 overexpression in T2DM occurs through key nodes that are potential therapeutic targets. We will define the crucial signaling intermediates downstream of the insulin receptor that normally suppress SULF2, as well as novel molecular mediators that affect SULF2 protein synthesis and degradation. Aim 3: Novel strategies to correct hepatic SULF2 overexpression in T2DM liver, and hence attenuate postprandial dyslipoproteinemia. Hypothesis 3: Inhibition of SULF2 is a viable therapeutic strategy, and we will take this concept beyond our previous ASO method. In Aim 3a, we will correct hepatic insulin signaling defects in T2DM liver in vivo, focusing on chaperones of NOX4 that are dysregulated in T2DM. Aim 3b will manipulate in vivo the novel participants in SULF2 regulation that we identify in Aim 2. Overall, these proposed Aims will substantially advance our molecular understanding and our abilities to correct the devastating burden of accelerated atherosclerosis in T2DM.

描述（由申请人提供）：绝大多数2型糖尿病（T2 DM）和相关综合征患者死于加速动脉粥样硬化。这些患者表现出惊人的持续性餐后富含TG的脂蛋白，称为“残余”， 每餐后的血浆。重要的是，残留物与人类心血管事件有关。由于对T2 DM患者中残留物清除延迟的基础了解甚少，因此没有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根本性的进展。首先，我们确定syndecan-1硫酸乙酰肝素蛋白聚糖（HSPG）作为残余受体。其次，使用阵列，我们发现正好一个基因的失调，这将损害syndecan-1在残留清除中的功能-即硫酸酯酶-2（Sulf 2），它在T2 DM肝脏中过表达10倍。SULF 2阻碍syndecan-1介导的肝细胞对残余物的催化作用。第三，我们刚刚发表了在T2 DM小鼠中，在玉米油灌胃后，体内抑制肝脏Sulf 2可抑制血浆TG波动。第四，我们发现胰岛素在转录后抑制SULF 2蛋白，并且由于N 0X 4功能缺陷损害AKT活化，这种作用在T2 DM肝脏中变得胰岛素抵抗。通过关注SULF 2，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。 目的1：硫酸酯酶-2在动脉粥样硬化中的作用：脂蛋白和非脂蛋白效应。假设1：SULF 2的抑制将通过两种作用减缓动脉粥样硬化：在肝脏中通过改善血浆脂蛋白谱和在动脉壁中通过阻碍局部促动脉粥样硬化信号通路，特别是Wnt。我们将研究SULF 2缺陷小鼠动脉粥样硬化病变的发展，培育成主要的动脉粥样硬化模型。SULF 2缺陷的有益影响将进一步加强我们的治疗重点。 目的2：T2 DM肝脏硫酸酯酶-2过表达的分子机制。假设2：T2 DM中肝脏SULF 2过表达通过作为潜在治疗靶点的关键节点发生。我们将定义通常抑制SULF 2的胰岛素受体下游的关键信号中间体，以及影响SULF 2蛋白合成和降解的新型分子介质。 目的3：纠正T2 DM肝脏中肝脏SULF 2过表达的新策略，从而减轻餐后血脂异常。假设3：抑制SULF 2是一种可行的治疗策略，我们将采用这一概念超越我们以前的阿索方法。在目标3a中，我们将在体内纠正T2 DM肝脏中的肝脏胰岛素信号传导缺陷，重点关注在T2 DM中失调的NOX 4的伴侣蛋白。目标3b将在体内操纵我们在目标2中鉴定的SULF 2调节的新参与者。 总的来说，这些提出的目标将大大提高我们的分子理解和我们的能力，以纠正T2 DM加速动脉粥样硬化的破坏性负担。