Treatment of Alcohol Induced Hepatic Injury with REV-ERB Ligands

用 REV-ERB 配体治疗酒精引起的肝损伤

• 批准号: 8444102
• 负责人: Thomas P Burris
• 金额: $ 27.17万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444102
• 关键词: Address; Adult; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Fatty Liver; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; American; Animal Model; Anti-Cytokine Therapy; Anti-Inflammatory Agents; Anti-inflammatory; C10; Cessation of life; Cholesterol; Chronic; Chronic Hepatitis; Circadian Rhythms; Cirrhosis; Clinical; Data; Development; Diet; Disease; Enzymes; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gene Expression; Genes; Glucose; Goals; Heavy Drinking; Hepatic; Hepatitis; Individual; Injury; Lead; Ligands; Liver; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Mus; Nuclear Receptors; Nutritional Support; Obesity; Pathogenesis; Patients; Pattern; Play; Prevention; Production; Public Health; Regulation; Relapse; Research; Risk Factors; Rodent; Role; Staging; Steroids; Symptoms; Testing; United States; alcohol abstinence; alcohol exposure; base; drinking; feeding; in vivo; innovation; lipid biosynthesis; lipid metabolism; liver injury; meetings; non-alcoholic fatty liver; novel; oxidation; public health relevance

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 ¿-oxidation. Furthermore, we have developed the first synthetic agonists (that have in vivo activity) for the nuclear receptors, REV-ERB¿ and REV-ERB¿, 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.

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 的范围从简单的脂肪变性（脂肪肝）到肝硬化，ALD 患者也可能有共同的非酒精性损伤的危险因素。酒精性脂肪肝病 (NAFLD) 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，大约 7.4% 的美国成年人符合这一标准。 1994 年和 2003 年酒精依赖的酒精滥用 DSMIV 标准中，44% 的肝病死亡是由于酒精滥用造成的，ALD 的发展阶段从脂肪肝（脂肪变性）开始，随后发展为酒精性肝炎，然后发展为慢性肝炎。纤维化（肝硬化）通常没有症状，戒酒约 6 周即可逆转，但最多可达 6 周。即使避免饮酒，5-15% 的脂肪变性患者仍会发展为肝炎和肝硬化。ALD 的第一步是发生肝脂肪变性，这是由于过量饮酒导致脂质代谢发生显着改变。没有直接解决酒精引起的脂肪肝发展的治疗方法。基因表达（时钟基因和代谢基因）昼夜节律的改变与肝脏脂质代谢的改变有关。对小鼠来说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的关键酶的基因和 ¿ -氧化。此外，我们还开发了第一个合成激动剂（具有体内活性）。 对于核受体，REV-ERB¿和 REV-ERB¿ ，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，还可以减少高脂肪喂养的小鼠的肝脏脂肪变性。因此，我们认为 REV-ERB 激动剂可能在 ALD 的治疗中有用，因为它们具有减少酒精引起的肝脂肪变性和预防 ALD 引起的肝损伤进一步进展的能力。为了实现我们的目标并检验我们的假设，我们提出了两个具体目标：1. 确定是否可以通过 REV-ERB 激动剂治疗来减少酒精引起的肝脂肪变性；2. 确定是否会引起基因表达昼夜节律的紊乱通过使用 REV-ERB 激动剂治疗，可以使慢性乙醇暴露导致的慢性酒精中毒恢复正常。这项研究具有高度创新性，因为它探讨了一种全新的 ALD 治疗机制。由于化合物（或其衍生物）可在临床上用于治疗ALD，因此影响很大。