Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects
Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin–angiotensin system are intimately linked. We evaluated the role of the renin–angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic st...
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| Veröffentlicht in: | European journal of pharmacology 2008-07, Vol.588 (2), p.316-324 |
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| creator | Kurita, Seiichiro Takamura, Toshinari Ota, Tsuguhito Matsuzawa-Nagata, Naoto Kita, Yuki Uno, Masafumi Nabemoto, Satoko Ishikura, Kazuhide Misu, Hirofumi Ando, Hitoshi Zen, Yoh Nakanuma, Yasuni Kaneko, Shuichi |
| description | Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin–angiotensin system are intimately linked. We evaluated the role of the renin–angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats and control Long–Evans Tokushima Otsuka (LETO) rats. Components of the renin–angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis. |
| doi_str_mv | 10.1016/j.ejphar.2008.04.028 |
| format | Article |
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Insulin resistance and the renin–angiotensin system are intimately linked. We evaluated the role of the renin–angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats and control Long–Evans Tokushima Otsuka (LETO) rats. Components of the renin–angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2008.04.028</identifier><identifier>PMID: 18501344</identifier><identifier>CODEN: EJPHAZ</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Angiotensin II type 1 receptor blocker ; Angiotensin II Type 1 Receptor Blockers - therapeutic use ; Animals ; Biological and medical sciences ; Choline Deficiency - complications ; Disease Models, Animal ; Fatty Acids - biosynthesis ; Fatty Liver - drug therapy ; Gastroenterology. Liver. Pancreas. Abdomen ; Imidazoles - pharmacology ; Imidazoles - therapeutic use ; Insulin Resistance ; Liver Cirrhosis, Experimental - prevention & control ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Methionine - deficiency ; NADPH oxidase ; Non-alcoholic steatohepatitis ; Other diseases. Semiology ; Oxidative Stress ; Pharmacology. Drug treatments ; Rats ; Rats, Long-Evans ; Renin–angiotensin system ; RNA, Messenger - analysis ; Sterol Regulatory Element Binding Protein 1 - genetics ; Tetrazoles - pharmacology ; Tetrazoles - therapeutic use ; Transforming Growth Factor beta - genetics ; Tumor Necrosis Factor-alpha - blood</subject><ispartof>European journal of pharmacology, 2008-07, Vol.588 (2), p.316-324</ispartof><rights>2008 Elsevier B.V.</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-3f15909567b89aee8d0cd7c52bab7314fa0cb692525b8784567c9ba7299ff0303</citedby><cites>FETCH-LOGICAL-c480t-3f15909567b89aee8d0cd7c52bab7314fa0cb692525b8784567c9ba7299ff0303</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejphar.2008.04.028$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3549,27923,27924,45994</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20431111$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18501344$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kurita, Seiichiro</creatorcontrib><creatorcontrib>Takamura, Toshinari</creatorcontrib><creatorcontrib>Ota, Tsuguhito</creatorcontrib><creatorcontrib>Matsuzawa-Nagata, Naoto</creatorcontrib><creatorcontrib>Kita, Yuki</creatorcontrib><creatorcontrib>Uno, Masafumi</creatorcontrib><creatorcontrib>Nabemoto, Satoko</creatorcontrib><creatorcontrib>Ishikura, Kazuhide</creatorcontrib><creatorcontrib>Misu, Hirofumi</creatorcontrib><creatorcontrib>Ando, Hitoshi</creatorcontrib><creatorcontrib>Zen, Yoh</creatorcontrib><creatorcontrib>Nakanuma, Yasuni</creatorcontrib><creatorcontrib>Kaneko, Shuichi</creatorcontrib><title>Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin–angiotensin system are intimately linked. We evaluated the role of the renin–angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats and control Long–Evans Tokushima Otsuka (LETO) rats. Components of the renin–angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis.</description><subject>Angiotensin II type 1 receptor blocker</subject><subject>Angiotensin II Type 1 Receptor Blockers - therapeutic use</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Choline Deficiency - complications</subject><subject>Disease Models, Animal</subject><subject>Fatty Acids - biosynthesis</subject><subject>Fatty Liver - drug therapy</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Imidazoles - pharmacology</subject><subject>Imidazoles - therapeutic use</subject><subject>Insulin Resistance</subject><subject>Liver Cirrhosis, Experimental - prevention & control</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Methionine - deficiency</subject><subject>NADPH oxidase</subject><subject>Non-alcoholic steatohepatitis</subject><subject>Other diseases. Semiology</subject><subject>Oxidative Stress</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Long-Evans</subject><subject>Renin–angiotensin system</subject><subject>RNA, Messenger - analysis</subject><subject>Sterol Regulatory Element Binding Protein 1 - genetics</subject><subject>Tetrazoles - pharmacology</subject><subject>Tetrazoles - therapeutic use</subject><subject>Transforming Growth Factor beta - genetics</subject><subject>Tumor Necrosis Factor-alpha - blood</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAQhq2Kim4Lb4CQL3BLGCfOxrkgoQooUqVe4GxNnHHjxYmD7a3E2-NqV3BjLtZI3z_y_zH2RkAtQOw_HGo6bDPGugFQNcgaGnXBdkL1QwW9aF6wHYCQVTMMwxW7TukAAN3QdC_ZlVAdiFbKHfv54BdKGDOuHBfyLkTMlDjyyVHG-JuXnS9hIs-D5WtYK_QmzME7w1MmzGGmDbPLLvE8x3B8nLnLiW-eXMgxbIUja8nk9IpdWvSJXp_fG_bjy-fvt3fV_cPXb7ef7isjFeSqtaIbYOj2_agGJFITmKk3XTPi2LdCWgQz7kuRphtVr2QBzTBiX4paCy20N-z96e4Ww68jpawXlwx5jyuFY9IlK9quFQWUJ9DEkFIkq7follJaC9DPkvVBnyTrZ8kapC6SS-zt-f5xXGj6FzpbLcC7M4DJoLcRV-PSX64B2Yoyhft44qjYeHIUdTKOVkOTi0WYnoL7_0_-ADdAnjw</recordid><startdate>20080707</startdate><enddate>20080707</enddate><creator>Kurita, Seiichiro</creator><creator>Takamura, Toshinari</creator><creator>Ota, Tsuguhito</creator><creator>Matsuzawa-Nagata, Naoto</creator><creator>Kita, Yuki</creator><creator>Uno, Masafumi</creator><creator>Nabemoto, Satoko</creator><creator>Ishikura, Kazuhide</creator><creator>Misu, Hirofumi</creator><creator>Ando, Hitoshi</creator><creator>Zen, Yoh</creator><creator>Nakanuma, Yasuni</creator><creator>Kaneko, Shuichi</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20080707</creationdate><title>Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects</title><author>Kurita, Seiichiro ; Takamura, Toshinari ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Uno, Masafumi ; Nabemoto, Satoko ; Ishikura, Kazuhide ; Misu, Hirofumi ; Ando, Hitoshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c480t-3f15909567b89aee8d0cd7c52bab7314fa0cb692525b8784567c9ba7299ff0303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Angiotensin II type 1 receptor blocker</topic><topic>Angiotensin II Type 1 Receptor Blockers - therapeutic use</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Choline Deficiency - complications</topic><topic>Disease Models, Animal</topic><topic>Fatty Acids - biosynthesis</topic><topic>Fatty Liver - drug therapy</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Imidazoles - pharmacology</topic><topic>Imidazoles - therapeutic use</topic><topic>Insulin Resistance</topic><topic>Liver Cirrhosis, Experimental - prevention & control</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Methionine - deficiency</topic><topic>NADPH oxidase</topic><topic>Non-alcoholic steatohepatitis</topic><topic>Other diseases. Semiology</topic><topic>Oxidative Stress</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Long-Evans</topic><topic>Renin–angiotensin system</topic><topic>RNA, Messenger - analysis</topic><topic>Sterol Regulatory Element Binding Protein 1 - genetics</topic><topic>Tetrazoles - pharmacology</topic><topic>Tetrazoles - therapeutic use</topic><topic>Transforming Growth Factor beta - genetics</topic><topic>Tumor Necrosis Factor-alpha - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kurita, Seiichiro</creatorcontrib><creatorcontrib>Takamura, Toshinari</creatorcontrib><creatorcontrib>Ota, Tsuguhito</creatorcontrib><creatorcontrib>Matsuzawa-Nagata, Naoto</creatorcontrib><creatorcontrib>Kita, Yuki</creatorcontrib><creatorcontrib>Uno, Masafumi</creatorcontrib><creatorcontrib>Nabemoto, Satoko</creatorcontrib><creatorcontrib>Ishikura, Kazuhide</creatorcontrib><creatorcontrib>Misu, Hirofumi</creatorcontrib><creatorcontrib>Ando, Hitoshi</creatorcontrib><creatorcontrib>Zen, Yoh</creatorcontrib><creatorcontrib>Nakanuma, Yasuni</creatorcontrib><creatorcontrib>Kaneko, Shuichi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kurita, Seiichiro</au><au>Takamura, Toshinari</au><au>Ota, Tsuguhito</au><au>Matsuzawa-Nagata, Naoto</au><au>Kita, Yuki</au><au>Uno, Masafumi</au><au>Nabemoto, Satoko</au><au>Ishikura, Kazuhide</au><au>Misu, Hirofumi</au><au>Ando, Hitoshi</au><au>Zen, Yoh</au><au>Nakanuma, Yasuni</au><au>Kaneko, Shuichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2008-07-07</date><risdate>2008</risdate><volume>588</volume><issue>2</issue><spage>316</spage><epage>324</epage><pages>316-324</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin–angiotensin system are intimately linked. We evaluated the role of the renin–angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats and control Long–Evans Tokushima Otsuka (LETO) rats. Components of the renin–angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>18501344</pmid><doi>10.1016/j.ejphar.2008.04.028</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Angiotensin II type 1 receptor blocker Angiotensin II Type 1 Receptor Blockers - therapeutic use Animals Biological and medical sciences Choline Deficiency - complications Disease Models, Animal Fatty Acids - biosynthesis Fatty Liver - drug therapy Gastroenterology. Liver. Pancreas. Abdomen Imidazoles - pharmacology Imidazoles - therapeutic use Insulin Resistance Liver Cirrhosis, Experimental - prevention & control Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Methionine - deficiency NADPH oxidase Non-alcoholic steatohepatitis Other diseases. Semiology Oxidative Stress Pharmacology. Drug treatments Rats Rats, Long-Evans Renin–angiotensin system RNA, Messenger - analysis Sterol Regulatory Element Binding Protein 1 - genetics Tetrazoles - pharmacology Tetrazoles - therapeutic use Transforming Growth Factor beta - genetics Tumor Necrosis Factor-alpha - blood |
| title | Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects |
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