Project 2: Regulation of lipid and glucose metabolism by ANGPTL3 in humans

人类遗传学、流行病学和随机临床试验数据表明， 降低LDL-C和TRL可降低CVD风险。抑制ANGPTL 3最近成为一种新的治疗方法， 降低LDL-C和TRL的方法，与其他降脂疗法不同， 因为ANGPTL 3缺陷的受试者具有改善的胰岛素敏感性。然而，完整的 在人类中抑制ANGPTL 3的代谢后果和负责ANGPTL 3代谢的细胞机制 ANGPTL 3缺乏的心脏代谢保护作用仍然未知。在这方面，项目2的目标将是： 确定ANGPTL 3在脂质和葡萄糖代谢中的作用。目的1将确定ANGPTL 3缺陷如何 在对照组和非对照组中使用体内示踪动力学研究， 既往招募的受试者具有单一或双等位基因ANGPTL 3功能丧失的家族 突变。我们将确定ANGPTL 3缺乏如何改变空腹和餐后血浆脂蛋白 除了脂肪组织和骨骼肌转录外， 与葡萄糖代谢相关的项目。目标2将使用来自具有完全免疫缺陷的人类的受试者特异性iPSC。 ANGPTL 3缺乏沿着与校正的同基因对照iPSC，以确定与iPSC相关的细胞机制。 ANGPTL 3与脂蛋白（包括RLP）和葡萄糖代谢的关系。与APOB的治疗靶点不同 （米泊美松）和MTTP（洛美他派），ANGPTL 3缺乏似乎减少肝脏VLDL分泌， 导致肝脂肪变性。此外，与其他批准的LDL降低疗法（他汀类药物，PSCK 9）不同， 抑制剂等），ANGPTL 3缺乏似乎降低了LDL胆固醇，而没有恶化T2 DM的风险。 总之，这些观察结果表明ANGPTL 3可能通过新的细胞内和细胞外途径起作用。 尚未发现的共同调节脂蛋白和葡萄糖的细胞外途径 新陈代谢.这里概述的研究准备发现这些细胞机制， 承诺扩大我们对人类生物学的理解，并确定更多的治疗目标， 治疗血脂异常，同时改善血糖水平。

Human genetic, epidemiologic, and randomized clinical trial data suggest that therapies that independently lower LDL-C and TRLs reduce the risk of CVD. Inhibiting ANGPTL3 recently emerged as a novel therapeutic approach for reducing both LDL-C and TRLs, which, unlike other lipid-lowering therapies, may protect against diabetes because ANGPTL3-deficient subjects have improved insulin sensitivity. However, the complete metabolic consequences of inhibiting ANGPTL3 in humans and the cellular mechanisms responsible for the cardiometabolic protective effect of ANGPTL3 deficiency remain unknown. In that context, Project 2’s aims will define the role of ANGPTL3 in lipid and glucose metabolism. Aim 1 will determine how ANGPTL3 deficiency alters lipoprotein and glucose metabolism in humans, using in vivo tracer kinetic studies in controls and in a previously recruited family with participants who have either single or biallelic ANGPTL3 loss of function mutations. We will determine how ANGPTL3 deficiency alters fasting and postprandial plasma lipoprotein particle number, size, and composition in addition to adipose tissue and skeletal muscle transcriptional programs related to glucose metabolism. Aim 2 will use subject-specific iPSCs from humans with complete ANGPTL3 deficiency along with corrected isogenic control iPSCs to determine the cellular mechanisms linking ANGPTL3 with lipoprotein (including RLP) and glucose metabolism. Unlike the therapeutic targets of APOB (mipomerson) and MTTP (lomitapide), ANGPTL3 deficiency appears to reduce hepatic VLDL secretion without leading to hepatic steatosis. In addition, unlike other approved LDL-lowering therapies (statins, PSCK9 inhibitors, etc), ANGPTL3 deficiency appears to reduce LDL cholesterol without worsening risk for T2DM. Together, these observations suggest that ANGPTL3 may be working through novel intracellular and extracellular pathways that are yet to be discovered which collectively modulate lipoprotein and glucose metabolism. The studies outlined here are poised to discover these cellular mechanisms which hold the promise to expand our understanding of human biology and identify additional therapeutic targets for the treatment of dyslipidemia while improving glucose levels.