PPARβ/δ activation protects against hepatic ischaemia-reperfusion injury

Liver Int. 2023 Dec;43(12):2808-2823. doi: 10.1111/liv.15760. Epub 2023 Oct 13.

Abstract

Background and aims: Hepatic ischaemia/reperfusion injury (HIRI) is a pathophysiological process that occurs during the liver resection and transplantation. Reportedly, peroxisome proliferator-activated receptor β/δ (PPARβ/δ) can ameliorate kidney and myocardial ischaemia/reperfusion injury. However, the effect of PPARβ/δ in HIRI remains unclear.

Methods: Mouse hepatic ischaemia/reperfusion (I/R) models were constructed for in vivo study. Primary hepatocytes and Kupffer cells (KCs) isolated from mice and cell anoxia/reoxygenation (A/R) injury model were constructed for in vitro study. Liver injury and inflammation were investigated. Small molecular compounds (GW0742 and GSK0660) and adenoviruses were used to interfere with PPARβ/δ.

Results: We found that PPARβ/δ expression was increased in the I/R and A/R models. Overexpression of PPARβ/δ in hepatocytes alleviated A/R-induced cell apoptosis, while knockdown of PPARβ/δ in hepatocytes aggravated A/R injury. Activation of PPARβ/δ by GW0742 protected against I/R-induced liver damage, inflammation and cell death, whereas inhibition of PPARβ/δ by GSK0660 had the opposite effects. Consistent results were obtained in mouse I/R models through the tail vein injection of adenovirus-mediated PPARβ/δ overexpression or knockdown vectors. Furthermore, knockdown and overexpression of PPARβ/δ in KCs aggravated and ameliorated A/R-induced hepatocyte injury, respectively. Gene ontology and gene set enrichment analysis showed that PPARβ/δ deletion was significantly enriched in the NF-κB pathway. PPARβ/δ inhibited the expression of p-IKBα and p-P65 and decreased NF-κB activity.

Conclusions: PPARβ/δ exerts anti-inflammatory and anti-apoptotic effects on HIRI by inhibiting the NF-κB pathway, and hepatocytes and KCs may play a synergistic role in this phenomenon. Thus, PPARβ/δ is a potential therapeutic target for HIRI.

Keywords: NF-κB pathway; apoptotic; hepatic ischaemia/reperfusion injury; inflammatory; peroxisome proliferator-activated receptor β/δ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Inflammation
  • Ischemia
  • Liver / metabolism
  • Mice
  • NF-kappa B / metabolism
  • PPAR delta* / genetics
  • PPAR delta* / metabolism
  • PPAR-beta* / genetics
  • PPAR-beta* / metabolism
  • Reperfusion Injury* / prevention & control
  • Thiazoles / pharmacology

Substances

  • PPAR-beta
  • GSK0660
  • NF-kappa B
  • PPAR delta
  • Thiazoles