CARBOHYDRATE-ETHANOL INTERACTIONS--DIET DELIVERY SYSTEMS

酒精中毒是世界范围内的重大公共卫生问题。酒精性肝病(ALD)包括从脂肪肝(脂肪变性)到酒精性肝炎和肝硬变的一系列病理生理状况。尽管脂肪变性在酗酒者中非常常见，但只有大约20%的酗酒者会出现严重的肝脏损伤。因此，大多数酗酒者的肝脏可以承受几十年的酗酒负担，而另一些人在酗酒几年后就会患上肝病。在这些易患疾病的个体中诱发ALD的因素以及保护大多数酗酒者免受ALD发展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，女性在较短的时间和较低的酒精摄入量后患上肝硬变。虽然很明显，饮酒的一些病理后果可以直接归因于酒精，但其他似乎是通过乙醇代谢物介导的间接影响，特别是乙醇代谢通过细胞色素P450酶CYP2E1催化的次要途径产生的自由基。有相当多的证据表明，乙醇/营养相互作用在许多导致酒精性肝病的过程中是重要的媒介。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，在酒精性肝损伤的病因学中，细胞色素P450-2E_1介导的自由基形成是主要因素，可能是通过激活局部巨噬细胞(库普弗细胞)释放促炎细胞因子。此外，我们推测饮食对乙醇诱导的肝毒性作用的基础是饮食对CYP2E1表达和诱导性的影响。这项提议是阿肯色州小石城的一个美国实验室与芬兰、瑞典和意大利的实验室共同努力的结果。总体目标是开发和验证一种新的低碳水化合物液体饮食大鼠酒精肝损伤模型，并与公认的灌胃模型进行比较。模型的比较将集中在可能影响ALD进程的三个重要变量上：1)饮食；2)性别；3)库普弗细胞的激活。

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.