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

Author

• Weilun Ai, University of Nebraska Medical CenterFollow

ORCID ID

0000-0001-6824-0877

Graduation Date

Fall 12-20-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Integrative Physiology & Molecular Medicine

First Advisor

Saraswathi Viswanathan

Abstract

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.

Comments

2024 Copyright, the authors

Rights

The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.

Recommended Citation

Ai, Weilun, "The Role of Thromboxane A2 Receptor in Alcohol-Associated Liver Disease and Alcohol-Associated Cardiomyopathy" (2024). Theses & Dissertations. 895.
https://digitalcommons.unmc.edu/etd/895