Oxidative stress and inflammation play an important role in the pathophysiological changes of liver diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes, thus playing a key role in protecting against oxidative damage. Cyclooxygenase-2 (COX-2) is a key enzyme in prostaglandin biosynthesis. Its expression has always been associated with the induction of inflammation, but we have shown that, in addition to possessing other benefits, the constitutive expression of COX-2 in hepatocytes is beneficial in reducing inflammation and oxidative stress in multiple liver diseases. In this review, we summarized the role of NRF2 as a main agent in the resolution of oxidative stress, the crucial role of NRF2 signaling pathways during the development of chronic liver diseases, and, finally we related its action to that of COX-2, where it appears to operate as its partner in providing a hepatoprotective effect.

Cyclooxygenase 2 (COX-2) is a key enzyme in prostanoid biosynthesis. The constitutive hepatocyte expression of COX-2 has a protective role in hepatic ischemia-reperfusion (I/R) injury (IRI), decreasing necrosis, reducing reactive oxygen species (ROS) levels, and increasing autophagy and antioxidant and anti-inflammatory response. The physiopathology of IRI directly impacts mitochondrial activity, causing ATP depletion and being the main source of ROS. Using genetically modified mice expressing human COX-2 (h-COX-2 Tg) specifically in hepatocytes, and performing I/R surgery on the liver, we demonstrate that COX-2 expression has a beneficial effect at the mitochondrial level. Mitochondria derived from h-COX-2 Tg mice livers have an increased respiratory rate associated with complex I electron-feeding pathways compared to Wild-type (Wt) littermates, without affecting complex I expression or assembly. Furthermore, Wt-derived mitochondria show a loss of mitochondrial membrane potential (ΔΨm) that correlates to increased proteolysis of fusion-related OPA1 through OMA1 protease activity. All these effects are not observed in h-COX-2 Tg mitochondria, which behave similarly to the Sham condition. These results suggest that COX-2 attenuates IRI at a mitochondrial level, preserving the proteolytic processing of OPA1, in addition to the maintenance of mitochondrial respiration.

Background and Aims: Cyclooxygenase‐2 (COX‐2) is involved in different liver diseases, but little is known about the significance of COX‐2 in cholestatic injury. This study was designed to elucidate the role of COX‐2 expression in hepatocytes during the pathogenesis of obstructive cholestasis.Methods: We used genetically modified mice constitutively expressing human COX‐2 in hepatocytes. Transgenic mice (hCOX‐2‐Tg) and their wild‐type (Wt) littermates were either subjected to a mid‐abdominal laparotomy or common bile duct ligation (BDL) for 2 or 5 days. Then, we explored the mechanisms underlying the role of COX‐2 and its derived prostaglandins in liver function, and the synthesis and excretion of bile acids (BA) in response to cholestatic liver injury.Results: After BDL, hCOX‐2‐Tg mice showed lower grades of hepatic necrosis and inflammation than Wt mice, in part by a reduced hepatic neutrophil recruitment associated with lower mRNA levels of pro‐inflammatory cytokines. Furthermore, hCOX‐2‐Tg mice displayed a differential metabolic pattern of BA synthesis that led to an improved clearance after BDL‐induced accumulation. In addition, an enhanced response to the BDL‐induced oxidative stress and hepatic apoptosis was observed. In vitro experiments using hepatic cells that stably express hCOX‐2 confirmed the cytoprotective role of prostaglandin E₂ against BA toxicity.Conclusions: Taken together, our data indicate that constitutive expression of COX‐2 in hepatocytes ameliorates cholestatic liver injury in mice by reducing inflammation and cell damage and by modulating BA metabolism, pointing to a role for COX‐2 as a defensive response against cholestasis‐derived BA accumulation and injury.