Leveraging arginine catabolism to treat metabolic diseases

利用精氨酸分解代谢治疗代谢性疾病

• 批准号: 10389803
• 负责人: Yiming Zhang
• 金额: $ 4.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389803
• 关键词: Leveraging; arginine; catabolism; treat; metabolic

ABSTRACT Intermittent fasting and caloric restriction are effective therapies against insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Yet, intensive lifestyle modifications are rarely sustainable. We made the provocative discovery that modulating systemic arginine status is sufficient to mimic the therapeutic effects of generalized caloric restriction on hepatic steatosis. This is clinically significant, because targeting arginine is a tractable pathway through which to treat metabolic disease. Accordingly, our long-term goal is to define the signaling cascades underlying adaptive hepatic glucose fasting, so that we can identify new therapies that leverage these pathways against IR, and NAFLD. Our unbiased transcriptomic screening in fasting mice identified a novel glucose fasting-induced effector: the amino acid hydrolase, arginase 2 (ARG2). Our new data demonstrate that forced hepatocyte-specific Arg2 expression reduces peripheral insulin resistance and hepatic steatosis in diabetic mice. Because hepatocyte arginine fate depends upon competition between ARG2 and the lysosomal arginine sensing machinery that dictate autophagic flux, and the pro-inflammatory enzyme, inducible nitric oxide synthase (iNOS), we hypothesize that fasting-induced hepatocyte ARG2 attenuates insulin resistance and hepatic steatosis by depleting hepatocyte arginine. To test this, we will: 1) examine pleiotropic therapeutic mechanisms of ARG2 action against insulin resistance and hepatic fat accumulation; 2) examine small-molecule and advanced biological therapeutics that mimic the therapeutic actions of ARG2 activation and 3) define their mechanistic underpinnings though single-cell sequencing. Completing these aims will: 1) establish arginine status as a determinant of metabolic homeostasis; 2) identify how modulating arginase activity impacts physiological outcomes; and 3) examine the efficacy and mechanisms of novel therapies against insulin resistance and NAFLD.

抽象的 间歇性禁食和热量限制是针对胰岛素抵抗（IR）和非酒精性的有效疗法 脂肪肝病（NAFLD）。然而，密集的生活方式修改很少是可持续的。我们做了挑衅 发现调节全身精氨酸状态足以模仿广义的治疗作用 对肝脂肪变性的热量限制。这具有临床意义，因为靶向精氨酸是一种可进行的 通过治疗代谢疾病的途径。因此，我们的长期目标是定义信号 级联反应的自适应肝葡萄糖禁食，因此我们可以识别出利用这些的新疗法 对IR和NAFLD的途径。我们在禁食小鼠中无偏的转录组筛查确定了一种小说 葡萄糖禁食诱导的效应子：氨基酸水解酶，精氨酸酶2（ARG2）。我们的新数据表明 强迫肝细胞特异性ARG2表达降低了外周胰岛素抵抗和肝脂肪变性 糖尿病小鼠。因为肝细胞精氨酸的命运取决于Arg2和溶酶体之间的竞争 指示自噬通量的精氨酸传感机制和促炎酶，可诱导的一氧化氮 合酶（iNOS），我们假设禁食诱导的肝细胞ARG2减弱了胰岛素抵抗和 肝脂肪变性通过耗尽肝细胞精氨酸。要测试这一点，我们将：1）检查多效性治疗 ARG2对胰岛素抵抗和肝脂肪积累的作用的机制； 2）检查小分子 以及模仿Arg2激活的治疗作用的先进生物学疗法，3）定义它们 机械基础是单细胞测序。完成这些目标将：1）建立精氨酸 作为代谢稳态决定因素的地位； 2）确定精氨酸酶活性如何影响 生理结果； 3）检查针对胰岛素的新型疗法的功效和机制 阻力和NAFLD。