Treatment of Alcohol Induced Hepatic Injury with REV-ERB Ligands

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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.