1. Thromboxane A2/thromboxane A2 receptor axis facilitates hepatic insulin resistance and steatosis through endoplasmic reticulum stress in non‐alcoholic fatty liver disease.
- Author
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Dai, Yufeng, Xu, Ruijie, Chen, Jinxiang, Fang, Jialong, Zhang, Hao, Li, Haitao, and Chen, Wei
- Subjects
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NON-alcoholic fatty liver disease , *INSULIN receptors , *ENDOPLASMIC reticulum , *INSULIN resistance , *INSULIN sensitivity , *FATTY degeneration , *FATTY liver - Abstract
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 A2 (TXA2), 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 TXA2/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 TXA2/TP receptor axis regulates insulin signalling and hepatocyte lipogenesis. Key Results: TXA2 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 TXA2/TP receptor axis disrupts insulin signalling by activating the Ca2+/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 TXA2/TP receptor axis directly promoted lipogenesis in primary hepatocytes and contributed to Kupffer cell inflammation. Conclusions and Implications: The TXA2/TP receptor axis facilitates insulin resistance through Ca2+/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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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