The Role of Thromboxane A2 Receptor in Alcohol-Associated Liver Disease and Alcohol-Associated Cardiomyopathy

Alcohol-associated liver disease (ALD) is a major health issue worldwide with limited effective treatment options. Thromboxane A2 receptor (TP-R), a G-protein-coupled receptor, is widely expressed in liver. Previous studies reported that an alcohol diet increased levels of TP-R ligands, thromboxane A2 and 8-isoprostane, in the mouse liver. However, the role of TP-R signaling in ALD remains unknown. In this thesis, we hypothesize that TP-R signaling pathway mediates ethanol-induced liver injury. To test this hypothesis, we used hepatocyte-specific TP-R knockout mice to determine the role of hepatocyte-specific TP-R in altering chronic ethanol diet-induced hepatic steatosis and inflammation. Our data suggest that deleting hepatocyte-specific TP-R exerts hepato-protective effects on preventing ethanol-induced liver injury by decreasing triglyceride accumulation, oxidative stress, and inflammatory response. Ethanol is not only hepatotoxic but also cardiotoxic. Heavy alcohol use induces alcohol-associated cardiomyopathy (ACM) which is characterized by mitochondrial dysfunction, abnormal fatty acid metabolism and transport, oxidative stress, and inflammation. ACM has become a leading cause of non-ischemic dilated cardiomyopathy. Using a model of chronic plus binge ethanol feeding, we examined the effects of blocking thromboxane A2 receptor (TP-R) on ethanol-induced early cardiac injury. Ethanol increased markers of NLR family pyrin domain containing 3 inflammasome (NLRP3) pathway, oxidative stress, inflammatory response, and pro-fibrogenic process in the myocardium. These ethanol-induced adverse effects were reversed by blocking TP-R activity.