2. Academic Validation
  3. PPARβ/δ activation protects against hepatic ischaemia-reperfusion injury

PPARβ/δ activation protects against hepatic ischaemia-reperfusion injury

  • Liver Int. 2023 Oct 13. doi: 10.1111/liv.15760.
Baolin Qian 1 2,  Chaoqun Wang 1 2,  Xiaozhuang Li 1 2,  Panfei Ma 1 2,  Liqian Dong 1 2,  Benqiang Shen 1 2,  Huibo Wu 1 2,  Nana Li 3,  Kai Kang 3,  Yong Ma 1 2
Affiliations

Affiliations

  • 1 Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 3 Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
PMID: 37833850 DOI: 10.1111/liv.15760
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.

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