Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice.
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.
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Omar
O
Motiño
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Noelia
N
Agra
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Rocío
R
Brea Contreras
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Marina
M
Domínguez-Moreno
Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Amadeo Vives 2, 28009 Madrid, Spain.
Carmelo
C
García-Monzón
Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Amadeo Vives 2, 28009 Madrid, Spain.
Javier
J
Vargas-Castrillón
Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina.
Cristina E
CE
Carnovale
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain.
Lisardo
L
Boscá
Instituto de Biomedicina de Valencia, IBV-CSIC, Jaume Roig 11, 46010 Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain.
Marta
M
Casado
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Rafael
R
Mayoral
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
M Pilar
MP
Valdecantos
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Monforte de Lemos 3-5, 28029 Madrid, Spain.
Ángela M
ÁM
Valverde
Instituto de Fisiología Experimental (IFISE-CONICET), Suipacha 570, 2000 Rosario, Argentina. Electronic address: frances@ifise-conicet.gov.ar.
Daniel E
DE
Francés
Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain. Electronic address: pmartins@iib.uam.es.
Paloma
P
Martín-Sanz
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000150:complications; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D018384:Oxidative Stress; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D011994:Recombinant Proteins; D008715:Methionine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
COX-2; Fibrosis; Inflammation; Liver; Steatohepatitis