The Effects of Hepatocyte-Specific Thromboxane A2 Receptor on Alcohol-Induced Adipose Tissue Inflammation

Backgrounds: The crosstalk of liver and adipose tissue (AT) is critical for the pathogenesis of alcohol-associated liver disease (ALD). Chronic alcohol use induces AT lipolysis, leading to the hepatic steatosis. Thromboxane A2 receptor (TP-R), a G-protein-coupled receptor, is widely expressed in the liver. Previous studies reported that pharmaceutical inhibition of TP-R signaling activation has hepato-protective effects on attenuating alcohol-induced inflammation and fibrosis in the rat livers. However, the potential involvement of liver-AT axis in mediating ALD and the role of hepatocyte-specific TP-R in the pathogenesis of ALD remain unclear. Therefore, we hypothesize that hepatocyte-specific TP-R mediates alcohol-induced AT dysfunction via liver-AT axis. Methods: To test this hypothesis, hepatocyte-specific TP-R knockout female mice (CKO) and their wild-type (WT) littermate mice were fed with the Lieber-DeCarli 5% (vol/vol) ethanol (ET) diet or isocaloric control diet (CON) for four weeks. Mice were divided into four groups: WT-CON (n=8), CKO-CON (n=8), WT-ET (n=8), and CKO-ET (n=8). Results: We noted that chronic alcohol feeding decreased visceral AT (VAT) mass ( P <0.05) and VAT adipocyte size ( P <0.01) in WT mice. In CKO mice, chronic alcohol consumption had no adverse effect on alterations in VAT mass and adipocyte size. Of note, VAT mRNA levels of M1 macrophage markers, including C-C motif chemokine ligand 2 ( P <0.05) and nitric oxide synthase 2 ( P <0.05) were increased in response to alcohol exposure in WT mice. These alcohol-induced pro-inflammatory effects were not found in VAT from CKO mice. Interestingly, deleting hepatocyte-specific TP-R increased mRNA level of arginase 1 ( P <0.05), a M2 macrophage marker, and uncoupling protein 1 ( P <0.05), an AT browning mediator regulating energy expenditure, in mouse VAT. Conclusion: These findings suggest that hepatocyte-specific TP-R plays an important role in regulating VAT inflammation and thermogenesis, thereby contributing to the development of ALD. Funding information: This study was supported by the NIH-NIAAA P50 award-Alcohol Center of Research-Nebraska (P50AA030407-5130). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.