Uncovering the Role of Retinoic Acid Receptor Beta in Alcoholic Liver Diseases

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Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the U.S, and together with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), is becoming the most common cause of hospitalization for liver transplantation. ALD, while initially asymptomatic, is characterized by steatosis and increased inflammation, and over time progresses toward a more serious condition, culminating in cirrhosis and liver failure. The pathogenesis of ALD is not fully understood which hinders the develop- ment of therapeutic options to manage not only alcohol-related disorders but also subsequent, fatal conditions such as liver failure. ALD shares molecular and histopathologic features with NAFLD/NASH, including increased steatosis, overproduction of oxygen reactive species (ROS), inflammation, and notably disruption of a key regulator of lipid metabolism, retinoic acid receptor beta (RARβ). Our research group has recently shown that disruption of RARβ signaling is critical in the development of NAFLD/NASH and the diabetic state in mice, and that treatment with a highly selective RARβ2 agonist, AC261066, resulted in improved glucose tolerance, and decreased steatosis, ROS, and inflammation. These findings underscore the central role of RARβ as a potential target to manage metabolic disorders and demonstrate that AC261066 could be a useful drug for treating these disorders. Based on the encouraging results obtained in NAFLD/NASH mice models, we hypothesize that the disruption of the RARβ signaling pathway is a key factor in the development of ALD and that treatment with AC261066 can prevent or reverse the progression of alcohol-related liver disorders. To test this hypothesis, we will use an in vitro model and an in vivo mouse model of chronic alcohol abuse that mimics ALD. We propose the following specific aims: Specific Aim (1): Determine if AC261066 prevents ethanol toxicity and determine if RARβ2 is essential for this effect. We will treat human hepatocytes with ethanol and measure metabolism and the expression of genes associated with oxidative stress and apoptosis in the presence or absence of AC261066. In a separate series of experiments, we will determine if the effects of AC261066 are dependent on RARβ2. Specific Aim (2): Determine if AC261066 prevents ethanol toxicity and explore the mechanisms of this effect in a murine model. For this aim we will use a mouse model of chronic ethanol intake that mimics ALD. We will measure the metabolic state prior to sacrifice and will follow with transcriptomic analyses using RNA-Seq, histology and pathology approaches.