Leveraging arginase biology against metabolic disease

摘要 间歇性禁食和热量限制是对抗胰岛素抵抗、非酒精性脂肪性肥胖和肥胖的有效疗法。 肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）。然而，密集的生活方式改变很少 可持续我们发现，调节全身精氨酸状态足以模拟 全面限热量对肝脂肪变性的治疗作用。这在临床上很重要， 因为靶向精氨酸是治疗代谢性疾病的一个容易处理的途径。因此，我们 长期目标是确定适应性肝葡萄糖禁食的信号级联，以便我们能够 确定利用这些途径对抗NAFLD和NASH的新疗法。我们的无偏转录组学 在禁食小鼠中的筛选鉴定出一种新的葡萄糖禁食诱导的效应物：氨基酸水解酶， 2（Arg2）。我们的新数据表明，强制肝细胞特异性Arg 2表达可降低外周血胰岛素 抵抗、肝脂肪变性和炎症。因为肝细胞精氨酸的命运取决于 Arg 2和决定自噬通量的溶酶体精氨酸传感机制之间的竞争， 促炎酶，诱导型一氧化氮合酶（iNOS），我们假设，禁食诱导 肝细胞Arg 2通过消耗肝细胞精氨酸来减轻肝脂肪变性和炎症。为了验证这个， 我们将：1）研究Arg 2对胰岛素抵抗和肝硬化的多效性治疗机制。 炎症; 2）检查小分子和先进的生物疗法，模拟治疗 Arg 2激活的作用和3）定义其机制基础。实现这些目标将：1）建立 精氨酸状态作为代谢稳态的决定因素; 2）确定调节精氨酸酶活性如何影响 细胞溶酶体传感及其生理结果;和3）检查新的免疫调节剂的功效和机制。 治疗NAFLD、NASH和胰岛素抵抗。

ABSTRACT Intermittent fasting and caloric restriction are effective therapies against insulin resistance, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). 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 NAFLD and NASH. 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, hepatic steatosis, and inflammation 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 hepatic steatosis and inflammation by depleting hepatocyte arginine. To test this, we will: 1) examine pleiotropic therapeutic mechanisms of Arg2 action against insulin resistance and hepatic inflammation; 2) examine small-molecule and advanced biological therapeutics that mimic the therapeutic actions of Arg2 activation and 3) define their mechanistic underpinnings. Completing these aims will: 1) establish arginine status as a determinant of metabolic homeostasis; 2) identify how modulating arginase activity impacts cellular lysosomal sensing and its physiological outcomes; and 3) examine efficacy and mechanisms of novel therapies to NAFLD, NASH and insulin resistance.