CARBOHYDRATE-ETHANOL INTERACTIONS--DIET DELIVERY SYSTEMS

酗酒是全世界关注的一个重大公共卫生问题。酒精性肝病（ALD）包括一系列病理生理状况，从脂肪肝（脂肪变性）到酒精性肝炎和肝硬化。虽然脂肪变性在酗酒者中很常见，但只有大约20%的酗酒者会出现严重的肝损伤。因此，大多数酗酒者的肝脏承受了大量饮酒数十年的负担，而另一些人仅在酗酒几年后就患上了肝脏疾病。在这些疾病易感个体中导致ALD的因素以及保护大多数酗酒者不患ALD的因素在很大程度上是未知的。此外，在易感性方面似乎存在显著的性别差异，与男性相比，女性在较短的时间和较低的酒精摄入量后患上肝硬化。虽然很明显，饮酒的一些病理后果可以直接归因于乙醇，但其他的似乎是通过乙醇代谢物介导的间接影响，特别是通过细胞色素P450酶CYP2E1催化的次要途径产生的乙醇代谢的自由基。有相当多的证据表明，乙醇/营养相互作用是导致ALD的许多过程中的重要介质。乙醇、不饱和脂肪和脂肪/碳水化合物比例的增加都会导致CYP2E1的诱导。我们的假设是，cyp2e1介导的自由基形成是乙醇诱导肝损伤病因学的主要因素，可能是通过激活局部巨噬细胞（Kupffer细胞）释放促炎细胞因子。此外，我们假设饮食对CYP2E1表达和乙醇诱导的影响是饮食对乙醇诱导的肝毒性发展的影响的基础。这项提议是阿肯色州小石城的一个美国实验室和芬兰、瑞典和意大利的实验室共同努力的结果。本研究的总体目标是建立和验证一种新的低碳水化合物液体饮食大鼠乙醇性肝损伤模型，并与已建立的灌胃-输注模型进行比较。模型的比较将集中在可能影响ALD病程的三个重要变量上：1)饮食；2)性别;3) Kupffer细胞的激活。

Alcoholism is of major public health concern worldwide. Alcoholic liver disease (ALD) encompasses a continuum of pathophysiologic conditions ranging from fatty liver (steatosis) to alcoholic hepatitis and cirrhosis. Although steatosis is very common among heavy drinkers, only about 20 percent of alcohol abusers develop serious liver damage. Thus, the liver of the majority of alcoholics withstands the burden of heavy drinking for decades while other individuals develop liver disease after only a few years of alcohol abuse. The factors that precipitate ALD in those disease-prone individuals and the factors that protect the majority of alcoholics from developing ALD are largely unknown. Furthermore, there appears to be a striking gender difference in susceptibility, with women developing cirrhosis after shorter periods and lower levels of alcohol intake than men. While it is clear that some of the pathological consequences of drinking can be attributed to ethanol directly, others appear to be indirect effects mediated via ethanol metabolites, in particular free radical produced as a consequence of ethanol metabolism via a minor pathway catalyzed by the cytochrome P450 enzyme CYP2E1. There is considerable evidence that ethanol/nutritional interactions are important mediators in many of the processes leading to ALD. Ethanol, unsaturated fat and increases in fat/carbohydrate ratio all result in induction of CYP2E1. It is our hypothesis that CYP2E1-mediated radical formation is the principal factor involved in the etiology of ethanol-induced liver injury, possibly through activation local macrophages (Kupffer cells) to release pro-inflammatory cytokines. Furthermore, we postulate that diet effects on CYP2E1 expression and inducibility by ethanol underlie the effects of diet on development of ethanol-induced hepatotoxicity. This proposal is the joint effort of one American laboratory in Little Rock, Arkansas and laboratories in Finland, Sweden and Italy. The overall goals are to develop and validate a new low carbohydrate liquid diet rat model for ethanol-induced liver injury in a side comparision with the well-established intragastric-infusion model. Comparison of the models will focus on three important variables which may influence the course of ALD: 1) diet; 2) gender; and 3) activation of Kupffer cells.