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加速动脉粥样硬化。这些患者每餐后血浆中富含TG的脂蛋白（称为“残余物”）持续存在。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，因此没有选择性靶向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，并且这种作用在T2 DM肝脏中成为胰岛素抵抗，与受损的AKT激活有关。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应用。 目的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SULF 2表达的正常调节将揭示潜在治疗靶点的关键节点。事实上，目前还不知道胰岛素如何抑制SULF 2的肝细胞表达。我们将通过从胰岛素受体和PI 3激酶-AKT通路向下（Aim 1a）和从SULF 2蛋白向上（Aim 1b）研究SULF 2调节。 目的2：纠正T2 DM db/db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2：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。在这里，我们将在体内操纵我们在目标1中确定的SULF 2调节中的新型AKT依赖性参与者。 总体而言，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餐后异常脂蛋白血症的破坏性健康负担。

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.