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

MOTIÑO O ; AGRA N; BREA CONTRERAS R; DOMÍNGUEZ-MORENO M; GARCÍA-MONZÓN C; VARGAS-CASTRILLÓN J; CARNOVALE CE; BOSCÁ L; CASADO M; MAYORAL R; VALDECANTOS MP; VALVERDE ÁM; FRANCÉS DE; MARTÍN-SANZ P

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2016 vol. 1862 p. 1710 - 1723

0925-4439

p { margin-bottom: 0.25cm; line-height: 120%; }Cyclooxygenase-2(COX-2) is involved in different liver diseases but little is knownabout the significance of COX-2 in the development and progression ofnon-alcoholic steatohepatitis (NASH). This study was designed toelucidate the role of COX-2 expression in hepatocytes in thepathogenesis of steatohepatitis and hepatic fibrosis. In the presentwork, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and theirwild-type (Wt) littermates were either fed methionine-and-cholinedeficient (MCD) diet to establish an experimental non-alcoholicsteatohepatitis (NASH) model or injected with carbon tetrachloride(CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg micefed MCD diet showed lower grades of steatosis, ballooning andinflammation than Wt mice, in part by reduced recruitment andinfiltration of hepatic macrophages, with a corresponding decrease inserum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tgmice showed a significant attenuation of the MCD diet-inducedincrease in oxidative stress and hepatic apoptosis observed in Wtmice. Even more, hCOX-2-Tg mice treated with CCl4 had significantlylower 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-2expression ameliorates NASH and liver fibrosis development in mice byreducing inflammation, oxidative stress and apoptosis and bymodulating activation of hepatic stellate cells, respectively,suggesting a possible protective role for COX-2 induction inNASH/NAFLD progression.p { margin-bottom: 0.25cm; line-height: 120%; Cyclooxygenase-2(COX-2) is involved in different liver diseases but little is knownabout the significance of COX-2 in the development and progression ofnon-alcoholic steatohepatitis (NASH). This study was designed toelucidate the role of COX-2 expression in hepatocytes in thepathogenesis of steatohepatitis and hepatic fibrosis. In the presentwork, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and theirwild-type (Wt) littermates were either fed methionine-and-cholinedeficient (MCD) diet to establish an experimental non-alcoholicsteatohepatitis (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 reducedrecruitment and infiltration of hepatic macrophages, with acorresponding decrease in serum levels of pro-inflammatory cytokines.Furthermore, hCOX-2-Tg mice showed a significant attenuation of theMCD diet-induced increase in oxidative stress and hepatic apoptosisobserved in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4had significantly lower stages of fibrosis and less hepatic contentof collagen, hydroxyproline and pro-fibrogenic markers than Wtcontrols. Collectively, our data indicates that constitutivehepatocyte COX-2 expression ameliorates NASH and liver fibrosisdevelopment in mice by reducing inflammation, oxidative stress andapoptosis and by modulating activation of hepatic stellate cells,respectively, suggesting a possible protective role for COX-2induction in NASH/NAFLD progression.<select><option value="af">Afrikaans</option><option value="sq">Albanian</option><option value="ar">Arabic</option><option value="hy">Armenian</option><option value="az">Azerbaijani</option><option value="eu">Basque</option><option value="be">Belarusian</option><option value="bg">Bulgarian</option><option value="ca">Catalan</option><option value="zh-CN">Chinese (Simplified)</option><option value="zh-TW">Chinese (Traditional)</option><option value="hr">Croatian</option><option value="cs">Czech</option><option value="da">Danish</option><option selected="da" value="auto">Detect language</option><option value="nl">Dutch</option><option value="en">English</option><option value="et">Estonian</option><option value="tl">Filipino</option><option value="fi">Finnish</option><option value="fr">French</option><option value="gl">Galician</option><option value="ka">Georgian</option><option value="de">German</option><option value="el">Greek</option><option value="ht">Haitian Creole</option><option value="iw">Hebrew</option><option value="hi">Hindi</option><option value="hu">Hungarian</option><option value="is">Icelandic</option><option value="id">Indonesian</option><option value="ga">Irish</option><option value="it">Italian</option><option value="ja">Japanese</option><option value="ko">Korean</option><option value="la">Latin</option><option value="lv">Latvian</option><option value="lt">Lithuanian</option><option value="mk">Macedonian</option><option value="ms">Malay</option><option value="mt">Maltese</option><option value="no">Norwegian</option><option value="fa">Persian</option><option value="pl">Polish</option><option value="pt">Portuguese</option><option value="ro">Romanian</option><option value="ru">Russian</option><option value="sr">Serbian</option><option value="sk">Slovak</option><option value="sl">Slovenian</option><option value="es">Spanish</option><option value="sw">Swahili</option><option value="sv">Swedish</option><option value="th">Thai</option><option value="tr">Turkish</option><option value="uk">Ukrainian</option><option value="ur">Urdu</option><option value="vi">Vietnamese</option><option value="cy">Welsh</option><option value="yi">Yiddish</option></select><span style="font-weight: bold; cursor: pointer; color: lightgrey;">⇄</span><select><option value="af">Afrikaans</option><option value="sq">Albanian</option><option value="ar">Arabic</option><option value="hy">Armenian</option><option value="az">Azerbaijani</option><option value="eu">Basque</option><option value="be">Belarusian</option><option value="bg">Bulgarian</option><option value="ca">Catalan</option><option value="zh-CN">Chinese (Simplified)</option><option value="zh-TW">Chinese (Traditional)</option><option value="hr">Croatian</option><option value="cs">Czech</option><option value="da">Danish</option><option value="nl">Dutch</option><option value="en">English</option><option value="et">Estonian</option><option value="tl">Filipino</option><option value="fi">Finnish</option><option value="fr">French</option><option value="gl">Galician</option><option value="ka">Georgian</option><option value="de">German</option><option value="el">Greek</option><option value="ht">Haitian Creole</option><option value="iw">Hebrew</option><option value="hi">Hindi</option><option selected="hi" value="hu">Hungarian</option><option value="is">Icelandic</option><option value="id">Indonesian</option><option value="ga">Irish</option><option value="it">Italian</option><option value="ja">Japanese</option><option value="ko">Korean</option><option value="la">Latin</option><option value="lv">Latvian</option><option value="lt">Lithuanian</option><option value="mk">Macedonian</option><option value="ms">Malay</option><option value="mt">Maltese</option><option value="no">Norwegian</option><option value="fa">Persian</option><option value="pl">Polish</option><option value="pt">Portuguese</option><option value="ro">Romanian</option><option value="ru">Russian</option><option value="sr">Serbian</option><option value="sk">Slovak</option><option value="sl">Slovenian</option><option value="es">Spanish</option><option value="sw">Swahili</option><option value="sv">Swedish</option><option value="th">Thai</option><option value="tr">Turkish</option><option value="uk">Ukrainian</option><option value="ur">Urdu</option><option value="vi">Vietnamese</option><option value="cy">Welsh</option><option value="yi">Yiddish</option></select><div style="text-align: left; background-color: rgb(235, 239, 249);">Detect language » Hungarian</div><div style="width: 444px; max-width: 444px; padding: 2px; min-height: 80px; border-width: 1px; border-style: solid; border-color: grey; background-color: rgb(255, 255, 255); text-align: justify;" /></div></body></html><select><option value="af">Afrikaans</option><option value="sq">Albanian</option><option value="ar">Arabic</option><option value="hy">Armenian</option><option value="az">Azerbaijani</option><option value="eu">Basque</option><option value="be">Belarusian</option><option value="bg">Bulgarian</option><option value="ca">Catalan</option><option value="zh-CN">Chinese (Simplified)</option><option value="zh-TW">Chinese (Traditional)</option><option value="hr">Croatian</option><option value="cs">Czech</option><option value="da">Danish</option><option selected="da" value="auto">Detect language</option><option value="nl">Dutch</option><option value="en">English</option><option value="et">Estonian</option><option value="tl">Filipino</option><option value="fi">Finnish</option><option value="fr">French</option><option value="gl">Galician</option><option value="ka">Georgian</option><option value="de">German</option><option value="el">Greek</option><option value="ht">Haitian Creole</option><option value="iw">Hebrew</option><option value="hi">Hindi</option><option value="hu">Hungarian</option><option value="is">Icelandic</option><option value="id">Indonesian</option><option value="ga">Irish</option><option value="it">Italian</option><option value="ja">Japanese</option><option value="ko">Korean</option><option value="la">Latin</option><option value="lv">Latvian</option><option value="lt">Lithuanian</option><option value="mk">Macedonian</option><option value="ms">Malay</option><option value="mt">Maltese</option><option value="no">Norwegian</option><option value="fa">Persian</option><option value="pl">Polish</option><option value="pt">Portuguese</option><option value="ro">Romanian</option><option value="ru">Russian</option><option value="sr">Serbian</option><option value="sk">Slovak</option><option value="sl">Slovenian</option><option value="es">Spanish</option><option value="sw">Swahili</option><option value="sv">Swedish</option><option value="th">Thai</option><option value="tr">Turkish</option><option value="uk">Ukrainian</option><option value="ur">Urdu</option><option value="vi">Vietnamese</option><option value="cy">Welsh</option><option value="yi">Yiddish</option></select><span style="font-weight: bold; cursor: pointer; color: lightgrey;">⇄</span><select><option value="af">Afrikaans</option><option value="sq">Albanian</option><option value="ar">Arabic</option><option value="hy">Armenian</option><option value="az">Azerbaijani</option><option value="eu">Basque</option><option value="be">Belarusian</option><option value="bg">Bulgarian</option><option value="ca">Catalan</option><option value="zh-CN">Chinese (Simplified)</option><option value="zh-TW">Chinese (Traditional)</option><option value="hr">Croatian</option><option value="cs">Czech</option><option value="da">Danish</option><option value="nl">Dutch</option><option value="en">English</option><option value="et">Estonian</option><option value="tl">Filipino</option><option value="fi">Finnish</option><option value="fr">French</option><option value="gl">Galician</option><option value="ka">Georgian</option><option value="de">German</option><option value="el">Greek</option><option value="ht">Haitian Creole</option><option value="iw">Hebrew</option><option value="hi">Hindi</option><option selected="hi" value="hu">Hungarian</option><option value="is">Icelandic</option><option value="id">Indonesian</option><option value="ga">Irish</option><option value="it">Italian</option><option value="ja">Japanese</option><option value="ko">Korean</option><option value="la">Latin</option><option value="lv">Latvian</option><option value="lt">Lithuanian</option><option value="mk">Macedonian</option><option value="ms">Malay</option><option value="mt">Maltese</option><option value="no">Norwegian</option><option value="fa">Persian</option><option value="pl">Polish</option><option value="pt">Portuguese</option><option value="ro">Romanian</option><option value="ru">Russian</option><option value="sr">Serbian</option><option value="sk">Slovak</option><option value="sl">Slovenian</option><option value="es">Spanish</option><option value="sw">Swahili</option><option value="sv">Swedish</option><option value="th">Thai</option><option value="tr">Turkish</option><option value="uk">Ukrainian</option><option value="ur">Urdu</option><option value="vi">Vietnamese</option><option value="cy">Welsh</option><option value="yi">Yiddish</option></select><div style="text-align: left; 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