Leveraging arginase biology against metabolic disease

利用精氨酸酶生物学对抗代谢疾病

• 批准号: 10583279
• 负责人: Brian Jesse DeBosch
• 金额: $ 43.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583279
• 关键词: ARG2 gene; Amino Acids; Arginine; Attenuated; Biological Response Modifier Therapy; Biology; Caloric Restriction; Data; Diabetic mouse; Enzymes; Fasting; Fatty Liver; Goals; Hepatic; Hepatocyte; Homeostasis; Hydrolase; Inflammation; Inflammatory; Insulin Resistance; Intermittent fasting; Life Style; Life Style Modification; Liver; Mediating; Metabolic; Metabolic Diseases; Mus; NOS2A gene; Obesity; Outcome; Pathway interactions; Patients; Peripheral; Physiological; Prediabetes syndrome; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; arginase; clinically significant; effective therapy; efficacy evaluation; fasting glucose; liver inflammation; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; screening; small molecule; transcriptomics

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.

摘要 间歇性禁食和热量限制是治疗胰岛素抵抗、非酒精性脂肪的有效方法 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 可持续发展。我们发现，调节全身精氨酸状态足以模拟 综合热量限制对肝脏脂肪变性的治疗作用。这在临床上具有重要意义， 因为靶向精氨酸是治疗代谢性疾病的一条容易处理的途径。因此，我们的 长期目标是确定适应性肝葡萄糖禁食背后的信号级联反应，以便我们能够 确定利用这些途径对抗非酒精性脂肪肝和非酒精性脂肪肝的新疗法。我们不偏不倚的转录 在禁食小鼠中的筛选发现了一种新的葡萄糖禁食诱导的效应：氨基酸水解酶，精氨酸酶 2(Arg2)。我们的新数据表明，强制肝细胞特异性Arg2表达会降低外周胰岛素 糖尿病小鼠的抵抗力、肝脏脂肪变性和炎症。因为肝细胞精氨酸的命运取决于 Arg2和决定自噬通量的溶酶体精氨酸传感机制之间的竞争，以及 促炎酶，诱导型一氧化氮合酶(INOS)，我们假设禁食诱导 肝细胞Arg2通过消耗肝细胞精氨酸来减轻肝脏脂肪变性和炎症。为了测试这一点， 我们将：1)研究Arg2对胰岛素抵抗和肝脏的多效性治疗机制 炎症；2)检验小分子和先进的生物疗法，模拟治疗 Arg2的激活作用和3)决定了它们的机制基础。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 细胞溶酶体感知及其生理结果；以及3)检测新型药物的疗效和机制 NAFLD、NASH和胰岛素抵抗的治疗。