Roles of ANGPTL3 and ANGPTL8 in Lipid and Energy Metabolism

血浆脂蛋白水平是冠心病(CHD)的主要危险因素。我们的实验室有 利用人类遗传学阐明循环脂蛋白的生理学和病理生理学，并鉴定 治疗干预的新靶点。在这里，我们主要关注血管生成素样蛋白3和8(Angptl3和 ANGPTL8)，对脂蛋白代谢有很强的作用。缺少Angptl3的人类有惊人的 泛脂血症，血浆低密度脂蛋白-胆固醇和甘油三酯(TG)水平显著降低。在最后一次 资助期我们表明，ANGPTL8(A8)是Angptl3(A3)的平行曲线，与其共同作用 将循环中的甘油三酯直接运输到周围组织的祖细胞。血管紧张素转换酶8缺乏降低血浆 人和小鼠体内的甘油三酯水平。 最近，我们的小组证明了A3和A8在能量代谢中都发挥着关键作用。 缺乏这两种基因的小鼠处于高代谢状态，体温升高，VO2增加，身体受损 脂肪堆积。与大量关于A3和A8的遗传差异对 循环中的脂蛋白，这两种蛋白在能量代谢中的作用几乎一无所知。在……里面 在这项建议中，我们将解决3个问题： 1)A3和A8在脂肪和能量代谢中的作用是什么？ 2)灭活A3和/或A8的潜在治疗作用是什么？ 3)血浆A3或A8水平的变化如何影响人类的其他代谢途径？ 在目标1中，转基因小鼠将被用来研究A3和A8对TG运输的作用 和能量新陈代谢。与A3不同，A8在脂肪组织和肝脏中都有表达；因此，我们将使用 组织特异性A8KO小鼠测定A8在两种组织中的功能。然后我们将调查 体温和基础体温显著和意外升高的代谢和分子基础 在缺乏A3和A8的小鼠中观察到代谢率。在目标2中，我们将使用单抗(MAbb)来 评估单独和联合灭活循环A3和A8的治疗潜力。在目标3中，我们将使用新的 研制抗A8抗体，建立一种灵敏、特异的检测血浆A8的酶联免疫吸附试验。为了这些 我们将利用我们在达拉斯建立的一项以人口为基础的研究， 达拉斯心脏研究，以确定血浆A8水平与代谢和心血管疾病的关系 在人类身上。这项资助中概述的研究所需的试剂和专业知识已在 我们的实验室。这些研究的成功完成将阐明一条重要的代谢途径，并可能 为新一代降血脂药物的开发提供动力 促进能源利用。 C/PPG 2015-Rp4-30行摘要

Plasma levels of lipoproteins are major risk factors for coronary heart disease (CHD). Our laboratory has used human genetics to elucidate the physiology and pathophysiology of circulating lipoproteins, and identify new targets for therapeutic intervention. Here we focus on the angiopoietin-like proteins 3 and 8 (ANGPTL3 and ANGPTL8), which exert powerful effects on lipoprotein metabolism. Humans lacking ANGPTL3 have striking panhypolipidemia, with marked reductions in plasma levels of LDL-cholesterol and triglycerides (TG). In the last funding period we showed that ANGPTL8 (A8) is a paralog of ANGPTL3 (A3)) that acts together with its progenitor to direct trafficking of circulating TG to peripheral tissues. Deficiency of ANGPTL8 reduces plasma levels of TG in both humans and mice. More recently, our group demonstrated that A3 and A8 both play a critical role in energy metabolism. Mice lacking the two genes are hypermetabolic, with increased body temperatures, increased VO2 and impaired fat accumulation. In contrast to the extensive literature on the effect of genetic differences in A3 and A8 on circulating lipoproteins, virtually nothing is known about the roles of these two proteins in energy metabolism. In this proposal, we will address 3 questions: 1) What are the roles of A3 and A8 in lipid and energy metabolism? 2) What is the potential therapeutic utility of inactivating A3 and/or A8? 3) How does variation in plasma A3 or A8 levels impact on other metabolic pathways humans? In Aim 1, genetically-modified mice will be used to investigate the actions of A3 and A8 on TG trafficking and energy metabolism. Unlike A3, A8 is expressed in adipose tissue as well as liver; therefore, we will use tissue-specific A8 KO mice to determine the function of A8 in the two tissues. We will then investigate the metabolic and molecular basis for the remarkable and unexpected increases in body temperature and basal metabolic rate observed in mice lacking both A3 and A8. In Aim 2 we will use monoclonal antibodies (mAbs) to assess the therapeutic potential of singly and jointly inactivating circulating A3 and A8. In Aim 3 we will use newly developed anti-A8 antibodies (Ab) to establish a sensitive and specific ELISA to quantify A8 in plasma. For these studies we will take advantage of a well-characterized population-based study that we established in Dallas, the Dallas Heart Study, to determine how plasma levels of A8 are related to metabolic and cardiovascular disease in humans. The reagents and expertise required for the studies outlined in this grant are already established in our laboratory. Successful completion of these studies will elucidate an important metabolic pathway and could provide the impetus for development of a new generation of lipid-lowering drugs that reduce plasma lipid levels and promote energy utilization. C/PPG 2015 – RP4 – 30-line Summary