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Leveraging arginine catabolism to treat metabolic diseases

利用精氨酸分解代谢治疗代谢性疾病

基本信息

批准号：
10560487
负责人：
Yiming Zhang
金额：
$ 4.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10560487
关键词：
ARG2 gene Aging Amino Acids Arginine Arginine deiminase Attenuated Biological Response Modifier Therapy Biology Caloric Restriction Calories Carbohydrates Cardiovascular system Catabolism Cells Chromatin Clinical Data Diabetes Mellitus Diabetic mouse Diet Disease Progression Disease Resistance Energy Metabolism Enzymes Expenditure FDA approved FGF21 gene Fasting Fatty Liver Fatty acid glycerol esters Genetic Genomics Glucose Glucose Transporter Goals Health Hepatic Hepatocyte Homeostasis Hydrolase Hydrolysis Inflammatory Insulin Resistance Intermittent fasting Knockout Mice Laboratories Life Style Life Style Modification Liver Longevity Mediating Metabolic Metabolic Diseases Metabolic syndrome Modeling Mus NOS2A gene Obesity Outcome Pathway interactions Patients Peripheral Persons Physiological Population Prediabetes syndrome Process Reagent Regulatory Pathway Signal Transduction Techniques Technology Testing Therapeutic Therapeutic Effect Thermogenesis Treatment Efficacy Work arginase carbohydrate transport cell type clinically significant defined contribution deprivation dietary effective therapy efficacy evaluation energy balance fasting glucose fibroblast growth factor 21 genome-wide improved innovation innovative technologies insulin sensitivity lifestyle intervention liver inflammation mortality mouse model non-alcoholic fatty liver disease novel novel therapeutic intervention novel therapeutics obesity genetics overexpression pharmacologic prevent response screening single cell sequencing small molecule transcription factor transcriptome transcriptomics

项目摘要

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