Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease

Background and Purpose Defective insulin signalling and dysfunction of the endoplasmic reticulum (ER), driven by excessive lipid accumulation in the liver, is a characteristic feature in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). Thromboxane A 2 (TXA 2 ), an arachidonic acid metabolite, is significantly elevated in obesity and plays a crucial role in hepatic gluconeogenesis and adipose tissue macrophage polarization. However, the role of liver TXA 2 /TP receptors in insulin resistance and lipid metabolism is largely unknown. Experimental Approach TP receptor knockout (TP −/− ) mice were generated and fed a high‐fat diet for 16 weeks. Insulin sensitivity, ER stress responses and hepatic lipid accumulation were assessed. Furthermore, we used primary hepatocytes to dissect the mechanisms by which the TXA 2 /TP receptor axis regulates insulin signalling and hepatocyte lipogenesis. Key Results TXA 2 was increased in diet‐induced obese mice, and depletion of TP receptors in adult mice improved systemic insulin resistance and hepatic steatosis. Mechanistically, we found that the TXA 2 /TP receptor axis disrupts insulin signalling by activating the Ca 2+ /calcium calmodulin‐dependent kinase II γ (CaMKIIγ)–protein kinase RNA‐like endoplasmic reticulum kinase (PERK)–C/EBP homologous protein (Chop)–tribbles‐like protein 3 (TRB3) axis in hepatocytes. In addition, our results revealed that the TXA 2 /TP receptor axis directly promoted lipogenesis in primary hepatocytes and contributed to Kupffer cell inflammation. Conclusions and Implications The TXA 2 /TP receptor axis facilitates insulin resistance through Ca 2+ /CaMKIIγ to activate PERK–Chop–TRB3 signalling. Inhibition of hepatocyte TP receptors improved hepatic steatosis and inflammation. The TP receptor is a new therapeutic target for NAFLD and metabolic syndrome.