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

饮酒会导致酒精性肝病(ALD)，这是美国发病率和死亡率的主要原因。此外，目前还不清楚为什么只有一些酗酒者会患上与临床相关的ALD。不幸的是，目前还没有FDA批准的针对ALD任何阶段的治疗方法，ALD的发病机制也不完全清楚。因此，研究ALD的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的促氧化环境，并增加肝脏的脂质过氧化(LPO)，从而产生脂质衍生的醛，如丙烯醛，这是最具活性和毒性的醛之一。丙烯醛主要通过谷胱甘肽-S-转移酶-PI(GSTP)催化结合成谷胱甘肽(GSH)来代谢/清除，除非被清除，否则会对细胞的关键功能产生不利影响。丙烯醛可以与细胞分子形成不可逆的共价加合物，造成有害后果；这种加合物与几种疾病有关。我们的数据表明，丙烯醛暴露于肝细胞可导致内质网应激、GSH耗竭和细胞凋亡，这些都是公认的ALD的病因。此外，我们的初步数据显示，饮酒下调了GSTP，并导致显著的肝脏丙烯醛生成/积累，这与小鼠的脂肪变性、炎症和肝脏损伤有关。这个项目将检验我们的假设，即丙烯醛关键地介导了酒精诱导的内质网应激和肝脏损伤，从而促进了ALD的发病。建议的研究将有助于阐明酒精性肝损伤的分子机制，并可能有助于确定新的治疗靶点和潜在的ALD干预措施。

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.