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的范围从单纯性脂肪变性(脂肪肝)到肝硬变，ALD患者也可能分享非酒精性脂肪性肝病(NAFLD)同时损伤的危险因素，这是一个重大的担忧，因为它与高脂肪饮食和肥胖在我们的文化中普遍存在。据估计，1994年约有7.4%的美国成年人符合DSMIV关于酒精依赖的酒精滥用标准，2003年，所有可归因于肝病的死亡中有44%是由酒精滥用引起的。酒精性肝病分阶段发展，从脂肪肝(脂肪变性)开始，依次发展为酒精性肝炎，然后是慢性肝炎合并纤维化(肝硬化)。酒精性脂肪肝最典型的症状是无症状，戒酒约6周是可逆的，但在多达5%-15%的脂肪变性患者中，即使戒酒，也会进展为肝炎和肝硬化。酒精性肝病的第一步是发生肝脏脂肪变性，这是由于过量饮酒导致脂质代谢的显著变化。目前，还没有直接针对酒精性脂肪肝发展的治疗方法。基因表达的昼夜节律的改变(时钟基因和代谢基因)与肝脏脂肪代谢的改变有关。我们假设给小鼠长期饮酒会导致正常昼夜节律的改变。 核心时钟基因以及编码涉及脂肪生成和氧化的关键酶的基因。此外，我们还开发了第一批合成激动剂(具有体内活性)。 对于核受体，REV-ERBα和REV-ERB？在哺乳动物生物钟的调节中起着关键作用。我们的初步数据表明，这些激动剂能够改变肝脏核心时钟和造脂基因的昼夜节律，此外，还能减轻高脂饮食小鼠的肝脏脂肪变性。因此，我们推测，REV-ERB激动剂可能在ALD的治疗中发挥作用，因为它们具有减少酒精诱导的肝脏脂肪变性和防止ALD导致的肝脏损伤进一步发展的潜在能力。为了达到我们的目标并验证我们的假设，我们提出了两个具体的目标：1.确定REV-ERB激动剂能否减轻酒精引起的肝脏脂肪变性；2.确定慢性酒精暴露引起的基因表达昼夜节律的紊乱是否可以通过REV-ERB激动剂治疗而正常化。这项拟议的研究具有很高的创新性，因为它研究了一种治疗ALD的全新机制。此外，由于这些化合物(或其衍生物)可能用于临床治疗ALD，因此拟议的研究具有很大的潜在影响。

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.