Chronic liver diseases is the 12th leading cause of death in the US, in which alcoholic liver disease (ALD) and Hepatitis C Virus (HCV) infection account for 44% and 37%, respectively. Of note, more than half of the HCV infected population meets the diagnostic criteria of alcoholism. This particular group of patients exhibits rapid progression of liver disease to cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms of this synergism are poorly understood and therefore effective management strategies are lacking. This proposed research is designed to understand how excessive alcohol consumption enhances the pathogenesis of chronic HCV infection. Ethanol (EtOH) metabolism in hepatocytes mainly employs two steps of the oxidative catabolic process in which alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play central roles. The ADH-ALDH pathway also governs metabolism of retinoid to its active metabolite, Retinoic Acid (RA). Therefore, excessive EtOH consumption impairs the production of RA. Emerging evidence suggests that RA regulates the expression of Interferon Stimulated Genes (ISGs), which play a central role in intercellular antiviral innate immunity. Thus, intrahepatic retinoid homeostasis is critical for HCV suppression. in the healthy liver store the majority of total body retinoid (Vitamn A) and are responsible for systemic distribution. The transformation of quiescent HSCs to myofibroblasts in ALD results in depletion of retinoid stores. These observations lead us to hypothesize that both 1) (Vitamin A) Hepatic Stellate Cells (HSC) EtOH-retinoid metabolic competition and 2) Loss of HSC derived retinoid impairs ISGs expression in hepatocytes, thereby allowing robust replication of HCV. In order to test these hypotheses, we propose the following aims;
(Aim1) Define the impact of EtOH-retinoid metabolic competition on hepatocyte antiviral innate immunity and (Aim2) Define the role of HSC derived retinoid on regulation of the innate defense program against HCV. The ultimate goal of this application is to define the critical role of retinoid on antiviral innate immunity and provide a better understanding of the pathogenesis of ALD-HCV synergism.
Public Health Statement Alcoholic Liver Diseases (ALD) and Hepatitis C virus (HCV) synergistically promote progression of liver disease to end stage cirrhosis and hepatocellular carcinoma. Our investigations aim to understand how ALD deregulates hepatic vitamin A homeostasis, resulting in impairment of the innate antiviral defense program. The results of this study will provide novel insights into the critical role of retinoids in suppression of the viral life cycle and offer guidance on an improved management strategy of HCV and its associated liver diseases.