Project Summary/Abstract Alcoholic liver disease (ALD) is responsible for more than half of all liver-related deaths in the United States. ALD and defined as a spectrum of disorders that begins with steatosis (fatty liver), that can progress to steatohepatitis, cirrhosis, and fibrotic end stage liver disease (ESLD). Current treatment options are focused on behavioral and pharmacological approaches for eliminating alcohol consumption and cravings. Individuals that struggle with alcohol abstinence face a higher risk of developing ALD cirrhosis, thus there is an urgent need for novel anti-ALD therapies. There is convincing evidence that the progression of ALD is driven by reductions and dysregulation of hepatic vitamin A (VA, retinol) metabolism and pathways. VA and related molecules are collectively called retinoids, which, acting through the VA metabolite retinoic acid (RA), and RA receptors (RAR α, β and γ), regulate the expression of genes involved in lipid metabolism, inflammation and anti- fibrotic pathways implicated in the development of ALD. I hypothesize that synthetic agonists for specific RARs, some of which are FDA approved for the treatment of some cancers, can activate and restore hepatic VA signaling pathways and have high therapeutic potential. I have generated preliminary data demonstrating that the specific RARβ2 agonist; AC261066, can significantly reduce hepatic steatosis, production of reactive oxygen species (ROS), and activation of scar forming hepatic stellate cells (HSCs) in a model of dietary induced non-alcoholic fatty liver disease (NAFLD). ALD and NAFLD share several clinical and molecular features, therefore this project will propose to determine i) the effectiveness of RARβ2 agonists on preventing HSC and liver fibrosis in a short- term, murine model of moderate alcohol intake, and ii) the therapeutic efficacy of RARβ2 agonists on reversing the clinical hallmarks of chronic alcohol abuse using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) murine model of chronic, binge alcohol liver injury. This project proposes an innovative approach to the development of ALD therapies by using agonists for RARβ which possesses similar anti-fibrotic properties of RA but, unlike RA, are not susceptible to ethanol-driven catabolism in ALD. Data from this proposal could lead to the development of RARβ agonists as therapies for ALD and other fibrotic liver disorders in humans.