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: 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
• 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

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（T2DM）及相关综合征患者死于动脉粥样硬化加速。这些患者在餐后的血浆中持续存在富含tg的脂蛋白，称为“残余物”。重要的是，残留物与人类心血管事件有关。由于对T2DM患者延迟残体清除的基础了解甚少，因此尚无选择性靶向这些有害颗粒的治疗策略。