Role of acrolein in hepatic ER stress adn injury in alcoholic liver disease

丙烯醛在酒精性肝病肝脏 ER 应激和损伤中的作用

• 批准号: 10116878
• 负责人: Swati Joshi-Barve
• 金额: $ 16.98万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116878
• 关键词: Acrolein; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Aldehydes; Apoptosis; Cell physiology; Centers of Research Excellence; Data; Disease; Environment; Etiology; FDA approved; Generations; Glutathione; Hepatic; Hepatocyte; Inflammation; Injury; Intervention; Lipid Peroxidation; Lipids; Liver; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Pathogenicity; Role; Testing; Toxicology; United States; adduct; chronic alcohol ingestion; clinically relevant; endoplasmic reticulum stress; glutathione S-transferase pi; liver injury; mortality; new therapeutic target; novel; targeted treatment

Alcohol consumption can cause alcoholic liver disease (ALD), which is a major cause of morbidity and mortality in the United States. Also, it remains unclear why only some heavy drinkers develop clinically relevant ALD. Unfortunately, there is no FDA-approved therapy for any stage of ALD, and the pathogenesis of ALD is not fully understood. Therefore, it is critical to investigate the underlying mechanisms and pathogenic mediators in order to identify novel targets and therapeutic strategies in ALD. Chronic alcohol consumption causes a prooxidant environment in the liver and increases hepatic lipid peroxidation (LPO), which produces lipid-derived aldehydes such as acrolein, one of the most reactive and toxic aldehydes. Acrolein is primarily metabolized/cleared by conjugation to glutathione (GSH) catalyzed by glutathione-S-transferase-Pi (GSTP); unless removed, acrolein can adversely impact key cellular functions. Acrolein can form covalent irreversible adducts with cellular molecules with detrimental consequences; such acrolein adducts are associated with several diseases. Our data show that acrolein exposure in hepatocytes causes endoplasmic reticulum (ER) stress, GSH depletion and apoptosis, all of which are recognized etiologic factors in ALD. Further, our preliminary data show alcohol consumption downregulates GSTP and causes significant hepatic acrolein generation/accumulation, which correlates with steatosis, inflammation and liver injury in mice. This project will test our hypothesis that acrolein critically mediates alcohol-induced ER stress and liver injury, thereby contributing to ALD pathogenesis. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury, and may help identify new therapeutic targets and potential interventions for ALD.

饮酒可导致酒精性肝病 (ALD)，这是美国发病和死亡的主要原因。此外，目前还不清楚为什么只有一些酗酒者会出现临床相关的酒精性肝病。不幸的是，FDA 还没有批准针对 ALD 任何阶段的治疗方法，并且 ALD 的发病机制尚不完全清楚。因此，研究潜在机制和致病介质以确定 ALD 的新靶点和治疗策略至关重要。长期饮酒会导致肝脏中产生促氧化环境，并增加肝脏脂质过氧化（LPO），从而产生脂质衍生的醛，例如丙烯醛，丙烯醛是最具反应性和毒性的醛之一。丙烯醛主要通过谷胱甘肽-S-转移酶-Pi (GSTP) 催化与谷胱甘肽 (GSH) 结合而被代谢/清除；除非去除，否则丙烯醛会对关键细胞功能产生不利影响。丙烯醛可以与细胞分子形成共价不可逆加合物，从而产生有害后果；这种丙烯醛加合物与多种疾病有关。我们的数据表明，肝细胞中丙烯醛暴露会导致内质网 (ER) 应激、GSH 耗竭和细胞凋亡，所有这些都是 ALD 中公认的病因因素。此外，我们的初步数据显示，饮酒会下调 GSTP 并导致肝脏丙烯醛显着生成/积累，这与小鼠的脂肪变性、炎症和肝损伤相关。该项目将检验我们的假设，即丙烯醛关键介导酒精引起的内质网应激和肝损伤，从而促进 ALD 发病机制。拟议的研究将有助于阐明酒精性肝损伤的分子机制，并可能有助于确定 ALD 的新治疗靶点和潜在干预措施。