Treatment of Alcohol Induced Hepatic Injury with REV-ERB Ligands

描述（由申请人提供）：酒精性肝病（ALD）是美国一个重要的公共卫生问题。ALD的范围从简单的脂肪变性（脂肪肝）到肝硬化，ALD患者也可能具有非酒精性脂肪性肝病（NAFLD）同时损伤的风险因素，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%的美国成年人符合DSMIV酒精滥用或酒精依赖的标准，2003年44%的肝病死亡是由于酒精滥用。ALD的发展阶段开始于脂肪肝（脂肪变性），随后进展为酒精性肝炎，然后是慢性肝炎伴纤维化（肝硬化）。酒精性脂肪肝是最典型的没有症状，是可逆的戒酒约6周，但在多达5-15%的脂肪变性的个人将进展到肝炎和肝硬化，即使消除酒精消费。ALD的第一步是肝脂肪变性的发展，这是由于过量饮酒介导的脂质代谢的显著改变。目前，没有直接解决酒精诱导的脂肪肝发展的疗法。基因表达（时钟基因和代谢基因）的昼夜节律的改变与肝脏中脂质代谢的改变相关。我们假设长期给小鼠服用酒精会导致正常昼夜节律的改变 核心时钟基因以及编码参与脂肪生成和β-氧化的关键酶的基因。此外，我们还开发了第一种合成激动剂（具有体内活性） 对于核受体REV-ERBα和REV-ERB β，其在哺乳动物生物钟的调节中起关键作用。我们的初步数据表明，这些激动剂能够改变肝脏中核心时钟和脂肪生成基因的昼夜节律，此外，还能减少高脂饮食小鼠的肝脏脂肪变性。因此，我们假设REV-ERB激动剂可能在ALD治疗中具有实用性，因为它们具有减少酒精诱导的肝脂肪变性和预防ALD引起的肝损伤进一步进展的潜在能力。为了解决我们的目标和测试我们的假设，我们提出了两个具体的目标：1。确定是否可以通过REV-ERB激动剂治疗减少酒精诱导的肝脂肪变性; 2.确定慢性乙醇暴露诱导的基因表达昼夜节律紊乱是否可以通过REV-ERB激动剂治疗恢复正常。这项研究具有高度创新性，因为它研究了一种全新的ALD治疗机制。此外，所提出的研究具有高影响力的潜力，因为化合物（或其衍生物）可在临床上用于治疗ALD。

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.