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引起的肝内蛋氨酸代谢变化的调节。以前，我们发现，饮食乙醇和叶酸缺乏饮食的组合都最大限度地干扰蛋氨酸代谢，加速发展的ALD在小型猪。拟议的研究的目的是通过证明ALD的生化和组织病理学特征可以通过向长期乙醇喂养的猪提供补充S-腺苷甲硫氨酸（SAM）或叶酸来预防或逆转，并证明这一假设。第一个具体目标是确定SAM或叶酸干预在预防和治疗小型猪ALD中的功效和代谢效应。第二个具体目标是研究蛋氨酸代谢异常对酒精性肝损伤的已知介质和信号通路的影响。在肝损伤发生期间，将小型猪饲喂含足够或缺乏叶酸的乙醇饲料，并补充或不补充SAM，在酒精性肝损伤发生后，补充或不补充SAM或叶酸。数据收集将包括血浆和肝脏中的甲硫氨酸代谢物、肝脏组织病理学、炎症、坏死和细胞凋亡的标志物、脂质、蛋白质和DNA氧化的产物、抗氧化酶以及细胞凋亡的信号途径。这些数据将被解释，以确认的作用，并建立在ALD的发病机制异常蛋氨酸代谢的潜在机制。在进一步了解蛋氨酸代谢物对肝损伤途径的相互作用的同时，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.