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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. [ABSTRACT FROM AUTHOR]

Targeting energy metabolism holds the potential to effectively treat a variety of malignant diseases, and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a key regulator of energy metabolism. However, PGC1α′s role in cancer, especially in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we reported that PGC1α was significantly downregulated in HCC cell lines and specimens. Moreover, reduced expression of PGC1α in tumor cells was correlated with poor prognosis. PGC1α overexpression substantially inhibited cell proliferation and induced apoptosis in vitro and in vivo. On the contrary, the knockdown of PGC1α produced the opposite effect. The mechanism was at least partially due to the upregulation of mitochondrial pyruvate carrier 1 (MPC1) caused by PGC1α, which promoted mitochondrial biogenesis by binding to nuclear respiratory factor 1 (NRF1). Consequently, the production of cellular reactive oxygen species (ROS) caused by mitochondrial oxidation was elevated above a critical threshold for survival. Furthermore, we found that PGC1α could enhance the antitumor activity of sorafenib and doxorubicin in HCC through ROS accumulation-mediated cell death. These results indicate that PGC1α/NRF1-MPC1 axis is involved in HCC progression and could be a promising target for HCC treatment. Image 1 • Low expression of PGC1α and MPC1 was associated with the poor prognosis of HCC. • PGC1α and MPC1 could inhibit HCC cell proliferation and induce apoptosis. • PGC1α/NRF1-MPC1 axis activates mitochondrial biogenesis and drives ROS production. • PGC1α/NRF1-MPC1 axis attenuates HCC progression. • PGC1α could enhance the sensitivity to sorafenib/doxorubicin treatment in HCC. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) α and γ have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPAR γ coactivator-1 α (PGC-1 α ), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1 α is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1 α is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1 α protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1 α aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPAR α and PPAR γ is increased or decreased by the overexpression or knockdown of PGC-1 α , respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPAR α (MK886) or PPAR γ (GW9662) can effectively decrease the protective effect of PGC-1 α against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1 α in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPAR α and PPAR γ . These data demonstrate that PGC-1 α protects against hepatic I/R injury, mainly by regulating the activation of PPAR α and PPAR γ . Thus, PGC-1 α may be a promising therapeutic target for the protection of the liver against I/R injury., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 Chaoqun Wang et al.)