Leveraging arginine catabolism to treat metabolic diseases

摘要 间歇性禁食和热量限制是对抗胰岛素抵抗(IR)和非酒精中毒的有效疗法 脂肪肝(NAFLD)。然而，密集的生活方式改变很少是可持续的。我们做出了挑衅性的 发现调节全身性精氨酸状态足以模拟全身性 限制热量对肝脏脂肪变性的影响。这在临床上具有重要意义，因为靶向精氨酸是一种容易处理的 治疗代谢性疾病的途径。因此，我们的长期目标是定义信令 适应性肝葡萄糖禁食潜在的级联作用，因此我们可以确定利用这些机制的新疗法 抗IR和NAFLD的途径。我们在禁食小鼠中进行的无偏见转录筛选发现了一个新的 葡萄糖禁食效应：氨基酸水解酶，精氨酸酶2(ARG2)。我们的新数据表明 强制表达肝细胞特异性Arg2降低外周胰岛素抵抗和肝脏脂肪变性 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 控制自噬通量的精氨酸传感机制，以及促炎酶、诱导型一氧化氮 合酶(INOS)，我们假设禁食诱导的肝细胞ARG2减轻胰岛素抵抗和 肝细胞精氨酸耗竭所致的肝脏脂肪变性。为了测试这一点，我们将：1)检查多效性治疗 Arg2抗胰岛素抵抗和肝脂肪蓄积的作用机制2)小分子物质检测 以及模拟ARG2激活的治疗行为的先进生物疗法，以及3)定义了它们的 通过单细胞测序的机械性基础。完成这些目标将：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 生理结果；以及3)检查针对胰岛素的新疗法的疗效和机制 耐药与非酒精性脂肪肝

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.