PPARβ/δ activation protects against hepatic ischaemia–reperfusion injury

Abstract

AbstractBackground and AimsHepatic 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.MethodsMouse 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.ResultsWe 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.ConclusionsPPARβ/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.