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Published on: February 10, 2015
Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
Omar Motiño1, Noelia Agra1, Rocío Brea Contreras1
1Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
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.
Insights
Constitutive hepatocyte cyclooxygenase-2 (COX-2) expression ameliorates non-alcoholic steatohepatitis (NASH) and liver fibrosis in mice. This protective role involves reducing inflammation, oxidative stress, and apoptosis, suggesting COX-2 induction may benefit NASH/NAFLD progression.
Area of Science:
- Hepatology
- Molecular Biology
- Inflammation Research
Background:
- Cyclooxygenase-2 (COX-2) role in liver diseases is recognized, but its specific involvement in non-alcoholic steatohepatitis (NASH) pathogenesis remains unclear.
- Understanding COX-2's function in hepatocytes is crucial for elucidating NASH and hepatic fibrosis development.
Purpose of the Study:
- To investigate the role of COX-2 expression specifically in hepatocytes during the development and progression of NASH and liver fibrosis.
- To determine if constitutive hepatocyte COX-2 expression impacts the severity of NASH and CCl4-induced liver fibrosis in a mouse model.
Main Methods:
- Utilized hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and wild-type (Wt) littermates.
- Established NASH model using a methionine-choline deficient (MCD) diet and liver fibrosis model using carbon tetrachloride (CCl4) injection.
- Assessed steatosis, inflammation, oxidative stress, apoptosis, and fibrosis markers.
Main Results:
- hCOX-2-Tg mice on MCD diet exhibited reduced steatosis, ballooning, and inflammation compared to Wt mice, with decreased macrophage infiltration and pro-inflammatory cytokines.
- MCD diet-induced oxidative stress and hepatic apoptosis were significantly attenuated in hCOX-2-Tg mice.
- CCl4-treated hCOX-2-Tg mice showed significantly lower fibrosis stages, collagen content, and pro-fibrogenic markers than Wt controls.
Conclusions:
- Constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis in mice.
- This protective effect is mediated by reduced inflammation, oxidative stress, apoptosis, and modulated hepatic stellate cell activation.
- COX-2 induction may play a protective role in the progression of NASH and non-alcoholic fatty liver disease (NAFLD).
