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.

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）的特征在于在缺乏脂肪肝的情况下肝细胞脂肪积累。 酒精或病毒病因，并且是从孤立性脂肪变性到 肝细胞癌（HCC）。据估计，NAFLD影响了世界近四分之一的人口。作为 过去几十年来，NAFLD相关HCC的发病率迅速上升，很明显， NAFLD是一种新兴的公共卫生危机，目前尚无批准的药物干预措施。 该项目将研究AKR 1a 1-一种最近发现的蛋白质脱亚硝基化酶-在 NAFLD的发病机制，通过询问其在通过可逆的S- 关键脂肪生成酶的亚硝基化。此外，AKR 1a 1作为一种新的治疗靶点， 预防NAFLD将被调查。为此，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鼠的饮食模型中的施用 同位素示踪研究，以询问对脂质代谢的整个途径和酶特异性影响; 树脂辅助捕获以评估酶的内源性S-亚硝基化;以及定点诱变以 确定S-亚硝基化的功能作用。总之，这项研究将为监管提供新的见解， 肝脏脂质代谢和NAFLD的病理生理学，并确定潜在的治疗靶点。