PPARγ Mediates Protective Effect against Hepatic Ischemia/Reperfusion Injury via NF-κB Pathway

Abstract

Background

Hepatic ischemia/reperfusion injury (HIRI) is an unavoidable complication in liver surgery, however its pathological process is still unclear. Therefore, in this study, the role and mechanism of peroxisome proliferator-activated receptor gamma (PPARγ) was investigated in HIRI.

Materials and Methods

We constructed mice models with HIRI and L02 cell models insulted hypoxia/re-oxygenation (H/R). PPARγ agonist rosiglitazone was administered prior to HIRI in mice and PPARγ-siRNA was to H/R treatment in L02 cells. Liver injury was measured by serum ALT, AST and LDH levels and performing H&E staining; the inflammatory injury was reflected by inflammatory markers IL-1β, IL-6 and TNF-α, which were assayed by Real-time PCR and Western blotting, MPO activity was determined using commercial kits; oxidative stress injury was evaluated by iNOS, MDA, SOD and GSH-PX levels; apoptosis was detected by cleaved-Caspase-3, TUNEL staining and flow cytometry; NF-κB signaling activation was reflected by phosphorylation of IκBα (p-IκBα) and nuclear translocation of NF-κB p65.

Results

The level of PPARγ expression was obviously down-regulated both in mice liver subjected to IRI and in L02 cells to H/R. Overexpression of PPARγ presented protective effect on HIRI by reducing serum levels of aminotransferase and hepatic necrosis, inhibiting inflammation and apoptosis and alleviating oxidative stress in vivo. But PPARγ-siRNA aggravate H/R insult by promoting inflammation and apoptosis in vitro. Mechanistically, the NF-κB pathway activity was increased with PPARγ down-regulation by PPARγ-siRNA. Importantly, inhibition of NF-κB signaling abolished PPARγ knockdown-mediated hepatic injury.

Conclusions

PPARγ present protective effects on HIRI by attenuating liver injury, inflammatory response, oxidative stress and apoptosis in vivo and in vitro, and its mechanism may be related to down-regulation of NF-κB signaling.

Keywords:

• peroxisome proliferator-activated receptor gamma
• hepatic ischemia reperfusion injury
• hepatocyte
• NF-κB pathway

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

This work was supported by the Health Committee Program of Qingpu District, Shanghai.