Sulfatase-2: Key mediator of atherogenic postprandial dyslipoproteinemia

绝大多数2型糖尿病(T2 DM)及相关综合征患者死于动脉粥样硬化加速。这些患者在每顿饭后的血浆中表现出显著的餐后富含甘油三酯的脂蛋白，也就是“残留物”。重要的是，残留物与人类心血管事件有关。由于T2 DM患者残留物清除延迟的基础一直知之甚少，因此没有治疗策略可用于选择性地针对这些有害颗粒。 我们的实验室在这方面取得了一系列根本性的进展。首先，我们鉴定了Syndecan-1硫酸乙酰肝素蛋白多糖(HSPG)是一个残存受体。其次，使用阵列，我们发现只有一个基因的失调会在残基清除中损害Syndecan-1的功能，即在T2 DM肝脏中过度表达10倍的硫酸酯酶-2(Sulf2)。SULF2抑制Syndecan-1介导的肝细胞对残留物的分解代谢。第三，我们刚刚发表了在体内抑制肝组织硫化物抑制T2 DM小鼠玉米油灌胃后的血浆甘油三酯漂移。第四，我们发现胰岛素在转录后抑制SULF2蛋白，并且这种作用在T2 DM肝脏中变得胰岛素抵抗，与AKT激活受损有关。通过关注SULF2，我们将提高我们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。 目的1：胰岛素正常抑制硫酸酶-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关键结节是潜在的治疗靶点。目前对胰岛素如何抑制肝细胞表达SULF2几乎一无所知。我们将从胰岛素受体和PI3激酶-AKT通路向下(目标1a)和从SULF2蛋白向上(目标1b)来研究SULF2的调节。 目的2：纠正T2 DM db/db肝脏中SULF2过表达的新策略，从而减轻餐后脂蛋白血症。假设2：抑制SULF2是一种可行的治疗策略，我们将把这一概念超越我们以前的ASO方法。在这里，我们将在体内操纵我们在目标1中确定的SULF2调控中依赖AKT的新参与者。 总体而言，这些拟议的目标将极大地促进我们对分子的理解，以及我们纠正T2 DM患者餐后脂蛋白血症造成的毁灭性健康负担的能力。

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.