AKR1a1 as a novel therapeutic target for Non-Alcoholic Fatty Liver Disease

AKR1a1作为非酒精性脂肪肝的新治疗靶点

• 批准号: 10385931
• 负责人: Nicholas Venetos
• 金额: $ 5.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10385931
• 关键词: ATP Citrate (pro-S)-Lyase; Ablation; Acetyl-CoA Carboxylase; Acute Renal Failure with Renal Papillary Necrosis; Affect; Amino Acids; Animals; Attenuated; Body Weight; CRISPR/Cas technology; Cell Culture Techniques; Cells; Choline; Coenzyme A; Coupled; Cysteine; Data; Diet; Dietary Administration; Disease; Drug Targeting; Enzymes; Equilibrium; Etiology; Family; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Genetic; Goals; Guidelines; Hepatic; Hepatocyte; High Fat Diet; Human body; Impairment; Incidence; Intervention; Isotopes; Knock-out; Knockout Mice; Label; Lipids; Liver; Liver diseases; Mass Spectrum Analysis; Mediating; Modeling; Modification; NADP; Nitric Oxide; Nitric Oxide Synthase; Obesity; Oxidoreductase; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Phenotype; Physiological; Plant Resins; Population; Prevention; Prevention therapy; Primary carcinoma of the liver cells; Protein Inhibition; Protein S; Proteins; Public Health; Regulation; Resistance; Risk; Role; S-Nitrosothiols; SKIL gene; Signal Transduction; Site-Directed Mutagenesis; Steatohepatitis; Sulfhydryl Compounds; Techniques; Tissues; Viral; Wild Type Mouse; diet-induced obesity; dietary; effective therapy; genome editing; in vivo; inhibitor; insight; knock-down; lipid biosynthesis; lipid metabolism; liver transplantation; member; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; prevent; problem drinker; protective effect; restoration; small molecule; small molecule inhibitor; therapeutic target

PROJECT SUMMARY/ABSTRACT Non-alcoholic Fatty Liver Disease (NAFLD) is characterized by hepatocyte fat accumulation in the absence of alcoholic or viral etiologies, and is part of a spectrum of disease ranging from isolated steatosis to hepatocellular carcinoma (HCC). NAFLD is estimated to affect nearly one-quarter of the world's population. As the incidence of NAFLD-associated HCC has risen rapidly over the past few decades, it has become clear that NAFLD is an emerging public health crisis for which there is currently no approved pharmacologic intervention. This project will investigate the role of AKR1a1—a recently discovered protein denitrosylase—in the pathogenesis of NAFLD through interrogation of its role in modulating hepatic lipid metabolism via reversible S- nitrosylation of key lipogenic enzymes. Further, the potential for AKR1a1 as a novel therapeutic target to prevent NAFLD will be investigated. To this end, the study will employ a variety of techniques including: CRISPR-Cas9 genome editing and administration of small molecule inhibitors in dietary models of murine NAFLD; isotope tracing studies to interrogate whole-pathway and enzyme-specific effects on lipid metabolism; resin-assisted capture to assess endogenous S-nitrosylation of enzymes; and site-directed mutagenesis to determine the functional role of S-nitrosylation. Together, this study will provide novel insight into the regulation of hepatic lipid metabolism and the pathophysiology of NAFLD, and identify potential therapeutic targets.

项目摘要/摘要 非酒精性脂肪性肝病(NAFLD)的特点是在缺乏 酒精或病毒病因，是一系列疾病的一部分，从孤立脂肪变性到 肝细胞癌(HCC)。据估计，非酒精性脂肪肝影响了全球近四分之一的人口。AS 在过去的几十年里，与NAFLD相关的肝癌的发病率迅速上升，这一点已经变得明显 非酒精性脂肪肝是一种新兴的公共卫生危机，目前还没有批准的药物干预措施。 该项目将研究AKR1a1--一种新近发现的蛋白质脱氮酶--在 S从可逆性角度探讨非酒精性脂肪性肝病的发病机制 关键的生脂酶的亚硝化。此外，AKR1a1作为一种新的治疗靶点的潜力 将对预防NAFLD进行调查。为此，这项研究将采用各种技术，包括： CRISPR-Cas9基因组编辑和小分子抑制剂在小鼠饮食模型中的应用 同位素示踪研究，以询问全程和酶对脂类代谢的特定影响； 树脂辅助捕捉法评估酶的内源S亚硝化；以及定点突变 确定S的功能作用--亚硝化。总而言之，这项研究将为监管提供新的见解 研究肝脂代谢和NAFLD的病理生理学，并确定潜在的治疗靶点。