Treatment of Alcohol Induced Hepatic Injury with REV-ERB Ligands

描述（由申请人提供）：酒精性肝病（ALD）在美国是一个重要的公共卫生问题。ALD范围从单纯脂肪变性（脂肪肝）到肝硬化，并且ALD患者也可能具有非酒精性脂肪性肝病（NAFLD）同时损伤的危险因素，这是一个值得关注的问题，因为它与我们文化中常见的高脂肪饮食和肥胖有关。据估计，1994年约有7.4%的成年美国人符合DSMIV关于酒精滥用或酒精依赖的标准，2003年44%的肝脏疾病死亡是由于酒精滥用。ALD的发展分阶段开始于脂肪肝（脂肪变性），随后发展为酒精性肝炎，然后是慢性肝纤维化（肝硬化）。酒精性脂肪肝最典型的症状是没有症状的，并且在戒酒约6周后是可逆的，但即使不饮酒，仍有多达5-15%的脂肪变性患者会发展为肝炎和肝硬化。ALD的第一步是肝脏脂肪变性的发展，这是由于过度饮酒介导的脂质代谢的显著改变。目前，还没有直接治疗酒精性脂肪肝的方法。基因表达昼夜节律的改变（时钟基因和代谢基因）与肝脏脂质代谢的改变有关。我们假设小鼠长期饮酒会导致正常昼夜节律的改变

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a significant public health concern in the United States. ALD ranges from simple steatosis (fatty liver) to cirrhosis and patients with ALD also may share risk factors for simultaneous injury from non-alcoholic fatty liver disease (NAFLD), which is a significant concern given its association with high fat diets and obesity common in our culture. Approximately 7.4% of adult Americans were estimated to meet the DSMIV criteria for alcohol abuse of alcohol dependence in 1994 and in 2003 44% of all deaths attributed to liver disease were due to alcohol abuse. ALD develops in stages beginning with fatty liver (steatosis) and sequentially progressing to alcoholic hepatitis and then chronic hepatitis with fibrosis (cirrhosis). Alcoholic fatty liver is most typically withot symptoms and is reversible with abstinence from alcohol for about 6 weeks, but in as many as 5-15% of individuals with steatosis will progress to hepatitis and cirrhosis even despite eliminating alcohol consumption. The first step in ALD is development of hepatic steatosis and this is due to significant alterations in lipid metabolism mediated by excessive alcohol consumption. Currently, there are no therapies that directly address development of alcohol-induced fatty liver. Alterations in the circadian rhythm of gene expression (both clock genes and metabolic genes) are associated with alterations in lipid metabolism in the liver. We hypothesize that chronic alcohol administration to mice will lead to alterations in the normal circadian rhythm of core clock genes as well as genes encoding key enzymes involved in lipogenesis and ß-oxidation. Furthermore, we have developed the first synthetic agonists (that have in vivo activity) for the nuclear receptors, REV-ERBα and REV-ERBß, which play a critical role in regulation of the mammalian clock. Our preliminary data indicates that these agonists have the ability to alter the circadian rhythm of both core clock and lipogenic genes in the liver and additionally, reduce hepatic steatosis in mice fed a high fat diet. Thus, we hypothesize that REV-ERB agonists may hold utility in treatment of ALD due to their potential ability to reduce alcohol-induced hepatic steatosis and prevention of further progression of hepatic injury due to ALD. In order to address our goal and test our hypothesis, we propose two specific aims: 1. Determine if hepatic steatosis induced by alcohol can be reduced by treatment with REV-ERB agonists and 2. Determine if disturbances in the circadian rhythm of gene expression induced by chronic ethanol exposure can be normalized by treatment with REV-ERB agonists. The proposed research is highly innovative since it examines a completely novel mechanism for treatment for ALD. Furthermore, the proposed research has the potential for high impact since the compounds (or derivatives thereof) may be used clinically to treat ALD.