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

Br J Pharmacol. 2024 Apr;181(7):967-986. doi: 10.1111/bph.16238. Epub 2023 Nov 8.

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.

Keywords: CaMKIIγ; ER stress; NAFLD; TXA2; hepatic insulin resistance.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Diet, High-Fat
  • Endoplasmic Reticulum Stress
  • Hepatocytes / metabolism
  • Inflammation / metabolism
  • Insulin Resistance*
  • Insulins* / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Receptors, Thromboxane A2, Prostaglandin H2 / metabolism
  • Receptors, Thromboxane A2, Prostaglandin H2 / therapeutic use
  • Thromboxane A2 / metabolism
  • Thromboxane A2 / therapeutic use

Substances

  • Receptors, Thromboxane A2, Prostaglandin H2
  • Thromboxane A2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Insulins