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.

摘要 间歇性禁食和热量限制是治疗胰岛素抵抗（IR）和非酒精性糖尿病的有效方法。 脂肪肝（NAFLD）。然而，密集的生活方式改变很少是可持续的。我们做了一个挑衅性的 发现调节全身精氨酸状态足以模拟全身性精氨酸的治疗效果。 热量限制对肝脂肪变性的影响。这在临床上是重要的，因为靶向精氨酸是一种易处理的方法。 治疗代谢性疾病的途径。因此，我们的长期目标是定义信令 级联反应的基础适应性肝葡萄糖禁食，使我们能够确定新的疗法，利用这些 抗IR和NAFLD的途径。我们在禁食小鼠中进行的无偏转录组筛选发现了一种新的 葡萄糖禁食诱导的效应物：氨基酸水解酶，精氨酸酶2（ARG 2）。我们的新数据表明， 强迫肝细胞特异性Arg 2表达可降低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命运取决于ARG 2和溶酶体之间的竞争， 精氨酸传感机制，决定自噬流量，和促炎酶，诱导型一氧化氮 通过诱导型一氧化氮合酶（iNOS）的表达，我们假设禁食诱导的肝细胞ARG 2减弱胰岛素抵抗， 肝细胞精氨酸耗竭导致肝脂肪变性。为了验证这一点，我们将：1）检查多效性治疗 ARG 2对抗胰岛素抵抗和肝脏脂肪蓄积的作用机制; 2）检查小分子 和模拟ARG 2激活的治疗作用的先进生物治疗剂，以及3）定义它们的 通过单细胞测序的机械基础。完成这些目标将：1）建立精氨酸 作为代谢稳态决定因素的状态; 2）确定调节β-淀粉酶活性如何影响 生理结果;和3）检查针对胰岛素的新疗法的功效和机制 抵抗和NAFLD。