PROJECT SUMMARY/ABSTRACT Alcohol abuse is a major health concern with a recently alarming increase in prevalence. Among the various complications associated with alcohol use disorder (AUD), alcohol-associated liver disease (ALD) is the most common and devastating. Mounting evidence supports a central role for inflammation and metabolic dysfunction in ALD. The long-term goal of this work is to understand the metabolic consequences of liver inflammation on alcohol consumption and ALD progression, and leverage this insight to develop novel treatment strategies. We have identified and characterized multiple points of crosstalk between interferon regulatory factor 3 (IRF3), a master regulator of innate immunity, and hepatic metabolism. Our preliminary data show that alcohol-induced IRF3 suppresses maximal fibroblast growth factor 21 (FGF21) expression and secretion by the liver. Using a novel phospho-mimetic mutant of IRF3, we found that transcriptionally active IRF3 abolishes alcohol-induced FGF21 secretion, while IRF3 deficiency enhances endogenous FGF21 secretion. Although IRF3 itself does not act as a transcriptional repressor of Fgf21, its metabolic effects are mediated through its transcriptional target, PLAGL1. The overall goal of this proposal is to identify the mechanisms responsible for IRF3-mediated FGF21 suppression and its impact on alcohol consumption and ALD. Our central hypothesis is that alcohol-induced IRF3 triggers transcription of PLAGL1, which functions as a novel repressor of Fgf21 expression, ultimately limiting its secretion. By targeting the IRF3-PLAGL1 inhibitory axis, we can release the brakes on Fgf21 transcription, increase endogenous FGF21 secretion, and enhance its beneficial effects on alcohol consumption and liver metabolism. In this proposal we will define the impact of IRF3-mediated FGF21 suppression on alcohol preference, motor impairment and sedation, as well as alcohol-induced steatosis and insulin resistance. Lastly, we will determine the mechanism by which the IRF3-PLAGL1 inhibitory axis regulates FGF21 levels, and subsequently alcohol consumption and ALD. Collectively, these studies will greatly advance our understanding of the metabolic consequences of inflammation on ALD progression. FGF21 is currently in clinical trials for obesity-induced metabolic dysfunction, and its beneficial role in AUD and ALD is undeniable. This work presents a critical opportunity to enhance the secretion of endogenous FGF21 in response to metabolic stressors such as obesity-inducing carbohydrate-rich diets and alcohol consumption.

PROJECT NARRATIVE Alcohol abuse and its associated liver diseases represent a significant public health challenge, and with no effective medical therapies, abstinence remains the mainstay for treatment. The liver secreted hormone, FGF21, is potently induced by ethanol and has profoundly beneficial effects on the brain, suppressing alcohol consumption, and on the liver, improving metabolic function and protecting against injury. We have identified a novel IRF3 inhibitory pathway that is a critical regulator of FGF21 transcription, and by targeting this pathway, we propose a therapeutic strategy for increasing FGF21 and its beneficial effects on alcohol abuse.