Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

Abstract

Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

“…Consistent with previous reports constitutive hepatic COX‐2 expression leads to lower plasmatic levels of proinflammatory cytokines (i.e., IL‐1β, IL‐6, and TNF‐α). hCOX‐2‐Tg mice presented an attenuated inflammatory response with lower levels of proinflammatory markers and higher levels of IL‐10, leading to a diminished hepatic IRI.…”

“…In hepatic IRI, a dead liver cell is usually present in a necrotic form, but malfunctioning programmed cell death is also observed in the hepatic IRI process . We found an attenuated response in the BAX/BCL‐2 ratio and caspase 3 activity in hCOX‐2‐Tg mice after IRI, in agreement with the reported antiapoptotic effect of COX‐2 activity …”

“…B). Our previous data showed lower levels of inflammatory markers and reduced hepatic leukocyte recruitment and infiltration in hCOX‐2‐Tg mice upon different liver injuries . There was no evidence of neutrophil accumulation after 4 hours of reperfusion.…”

Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet

“…Lab, Rosario, Argentina). Samples of liver tissue were fixed in 4% buffered formalin for paraffin preparation and then were used for histopathology assessment [17].…”

Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives

“…In line with this, COX-2-Tg mice fed MCD diet are protected against NASH when compared with the Wt counterparts, essentially through a mechanism that involves a lesser recruitment of circulating immune cells and, as a consequence, a minor presence of pro-inflammatory factors in the liver, resulting in a minor activation of the pro-fibrogenic cells present in the tissue, such as HSCs. Furthermore, these COX-2-Tg mice treated with a classic pro-fibrogenic insult as is CCl 4 exhibited a significant protection against fibrosis progression as reflected by lower synthesis of hepatic collagen and accumulation of hydroxyproline when compared with the Wt controls[40]. Figure 2 summarizes the main findings observed in the animal models carrying a COX-2 transgene.…”