SAMe and Folate Deficiency in Alcoholic Mircropigs

描述(申请人提供)：拟议研究的总体假设是，酒精性肝病(ALD)的发病机制是由慢性酒精摄入导致的肝内蛋氨酸代谢的变化调节的。在此之前，我们发现饮食中添加乙醇和缺乏叶酸的饮食可以最大限度地增加蛋氨酸代谢的扰动，并加速小型猪ALD的发生。本研究的目的是为了验证这一假说，证明通过补充S-腺苷蛋氨酸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小型猪ALD中的疗效和代谢影响。第二个具体目的是研究蛋氨酸代谢异常对已知的酒精性肝损伤介质和信号通路的影响。在发生肝损伤时，饲喂叶酸充足或不足、添加或不添加SAM的乙醇日粮；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、坏死和凋亡的标记物、脂质、蛋白质和DNA氧化的产物、抗氧化酶和细胞凋亡的信号通路。这些数据将被解释以确认蛋氨酸代谢异常在ALD发病机制中的作用并建立潜在的机制。在进一步了解蛋氨酸代谢产物在肝损伤途径上的相互作用的同时，该项目可能会建立预防和治疗ALD的新方法。

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.