SAMe and Folate Deficiency in Alcoholic Mircropigs

描述（由申请人提供）：拟议研究的总体假设是酒精性肝病（ALD）的发病机制受慢性乙醇消耗导致的肝内蛋氨酸代谢变化的调节。在此之前，我们发现饲粮中乙醇和缺乏叶酸的饲粮组合会最大程度地扰乱微猪的蛋氨酸代谢，并加速ALD的发展。本研究的目的是为了证明这一假设，即通过向长期乙醇饲养的猪添加s -腺苷蛋氨酸（SAM）或叶酸，可以预防或逆转ALD的生化和组织病理学特征。第一个具体目的是确定SAM或叶酸干预在预防和治疗微猪ALD中的功效和代谢影响。第二个具体目的是研究蛋氨酸代谢异常对酒精性肝损伤已知介质和信号通路的影响。在肝损伤发生期间，将给小猪饲喂叶酸充足或缺乏的乙醇饲粮，并在肝损伤发生后添加或不添加SAM或叶酸，在酒精性肝损伤发生后添加或不添加SAM或叶酸。数据收集将包括血浆和肝脏中的蛋氨酸代谢物、肝脏组织病理学、炎症、坏死和凋亡标志物、脂质、蛋白质和DNA氧化产物、抗氧化酶和凋亡信号通路。这些数据将被解释以确认蛋氨酸代谢异常在ALD发病中的作用并建立潜在的机制。在进一步了解蛋氨酸代谢物在肝损伤途径中的相互作用的同时，该项目可能为ALD的预防和治疗开辟新的途径。

DESCRIPTION (provided by applicant): The overall hypothesis of the proposed research is that the pathogenesis of alcoholic liver disease (ALD) is regulated by changes in intrahepatic methionine metabolism that result from chronic ethanol consumption. Previously, we found that the combination of dietary ethanol and a folate deficient diet both maximized perturbations in methionine metabolism and accelerated the development of ALD in micropigs. The objective of the proposed research is to prove the hypothesis by demonstrating that the biochemical and histopathological features of ALD can be prevented or reversed by provision of supplemental S-adenosylmethionine (SAM) or folic acid to pigs maintained on chronic ethanol feeding with and without folate deficient diet. The first specific aim is to determine the efficacy and metabolic effects of intervention with SAM or folic acid in the prevention and treatment of ALD in micropigs. The second specific aim is to study the effects of abnormal methionine metabolism on known mediators and signal pathways of alcoholic liver injury. Micropigs will be fed diets with ethanol that are either folate sufficient or deficient and with or without supplemental SAM during development of liver injury, and with or without supplemental SAM or folic acid after development of alcoholic liver injury. Data collection will include methionine metabolites in plasma and liver, liver histopathology, markers of inflammation, necrosis, and apoptosis, products of lipid, protein, and DNA oxidation, antioxidant enzymes, and signal pathways of apoptosis. The data will be interpreted to confirm the role and establish potential mechanisms for abnormal methionine metabolism in the pathogenesis of ALD. While furthering understanding of interactions of methionine metabolites on pathways of liver injury, the project may establish novel approaches to the prevention and treatment of ALD.