Liver-Specific Inactivation of the Nrf1 Gene in Adult Mouse Leads to Nonalcoholic Steatohepatitis and Hepatic Neoplasia
Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, a...
Gespeichert in:
| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-03, Vol.102 (11), p.4120-4125 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 4125 |
|---|---|
| container_issue | 11 |
| container_start_page | 4120 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 102 |
| creator | Xu, Zhenrong Chen, Linyun Leung, Laura T. S. Benedict Yen Lee, Candy Chan, Jefferson Y. Kan, Yuet Wai |
| description | Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer. |
| doi_str_mv | 10.1073/pnas.0500660102 |
| format | Article |
| fullrecord | <record><control><sourceid>jstor_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_17616927</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>3374876</jstor_id><sourcerecordid>3374876</sourcerecordid><originalsourceid>FETCH-LOGICAL-c592t-d9d093c1c1b2b7d09a3eea1f3661f98ca91b1d2cfa39c17560a244a840ceddab3</originalsourceid><addsrcrecordid>eNqF0UFv0zAUB_AIgVgZnLkgsDggLtnesxM7PnCYJtgmlXIYnC3XcairNM5sp8C3x6XVChzgZFv-vb_s94riOcIZgmDn46DjGdQAnAMCfVDMECSWvJLwsJgBUFE2Fa1OiicxrgFA1g08Lk6wFqxhjZwV3-Zua0N5O1rjOmfIzaBNcludnB-I70haWbIIHZIrO1jiBnLRTn0iH_0ULZlb3UaSPFn4QffGr3yfI26T1cmv7JhDkotEDy25_nUyZGH92Ovo9NPiUaf7aJ8d1tPiy4f3ny-vy_mnq5vLi3lpaklT2coWJDNocEmXIu81s1ZjxzjHTjZGS1xiS02nmTQoag6aVpVuKjC2bfWSnRbv9rnjtNzY1tghBd2rMbiNDj-U1079eTO4lfrqt6quq4bWuf7NoT74u8nGpDYuGtv3erC5B4qLmiJn9L8QBUcuqcjw9V9w7aeQ-xcVBWQCGsEyOt8jE3yMwXb3L0ZQu8mr3eTVcfK54uXvHz36w6gzeHUAu8pjHFWIqkIKWbz9t1Dd1PfJfk-ZvtjTdUw-3FvGRNUIzn4CXXjNLw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>201370873</pqid></control><display><type>article</type><title>Liver-Specific Inactivation of the Nrf1 Gene in Adult Mouse Leads to Nonalcoholic Steatohepatitis and Hepatic Neoplasia</title><source>Jstor Complete Legacy</source><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Xu, Zhenrong ; Chen, Linyun ; Leung, Laura ; T. S. Benedict Yen ; Lee, Candy ; Chan, Jefferson Y. ; Kan, Yuet Wai</creator><creatorcontrib>Xu, Zhenrong ; Chen, Linyun ; Leung, Laura ; T. S. Benedict Yen ; Lee, Candy ; Chan, Jefferson Y. ; Kan, Yuet Wai</creatorcontrib><description>Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0500660102</identifier><identifier>PMID: 15738389</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Alleles ; Animals ; Antioxidants - metabolism ; Apoptosis ; Biological Sciences ; Cell growth ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Fatty acids ; Fatty Acids - metabolism ; Gene expression ; Hepatitis - genetics ; Hepatitis - metabolism ; Hepatocytes ; Inflammation ; Lipids ; Liver ; Liver - metabolism ; Liver Neoplasms - etiology ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Mice ; Mice, Knockout ; Microsomes, Liver - metabolism ; Mutation ; Nuclear Respiratory Factor 1 ; Nuclear Respiratory Factors ; Oxidation ; Oxidation-Reduction ; Oxidative stress ; Reactive Oxygen Species - metabolism ; Response Elements - physiology ; Reverse transcriptase polymerase chain reaction ; Rodents ; Trans-Activators - genetics ; Trans-Activators - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2005-03, Vol.102 (11), p.4120-4125</ispartof><rights>Copyright 1993/2005 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 15, 2005</rights><rights>Copyright © 2005, The National Academy of Sciences 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-d9d093c1c1b2b7d09a3eea1f3661f98ca91b1d2cfa39c17560a244a840ceddab3</citedby><cites>FETCH-LOGICAL-c592t-d9d093c1c1b2b7d09a3eea1f3661f98ca91b1d2cfa39c17560a244a840ceddab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/102/11.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3374876$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3374876$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15738389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Zhenrong</creatorcontrib><creatorcontrib>Chen, Linyun</creatorcontrib><creatorcontrib>Leung, Laura</creatorcontrib><creatorcontrib>T. S. Benedict Yen</creatorcontrib><creatorcontrib>Lee, Candy</creatorcontrib><creatorcontrib>Chan, Jefferson Y.</creatorcontrib><creatorcontrib>Kan, Yuet Wai</creatorcontrib><title>Liver-Specific Inactivation of the Nrf1 Gene in Adult Mouse Leads to Nonalcoholic Steatohepatitis and Hepatic Neoplasia</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer.</description><subject>Alleles</subject><subject>Animals</subject><subject>Antioxidants - metabolism</subject><subject>Apoptosis</subject><subject>Biological Sciences</subject><subject>Cell growth</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Fatty acids</subject><subject>Fatty Acids - metabolism</subject><subject>Gene expression</subject><subject>Hepatitis - genetics</subject><subject>Hepatitis - metabolism</subject><subject>Hepatocytes</subject><subject>Inflammation</subject><subject>Lipids</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver Neoplasms - etiology</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microsomes, Liver - metabolism</subject><subject>Mutation</subject><subject>Nuclear Respiratory Factor 1</subject><subject>Nuclear Respiratory Factors</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Oxidative stress</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Response Elements - physiology</subject><subject>Reverse transcriptase polymerase chain reaction</subject><subject>Rodents</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0UFv0zAUB_AIgVgZnLkgsDggLtnesxM7PnCYJtgmlXIYnC3XcairNM5sp8C3x6XVChzgZFv-vb_s94riOcIZgmDn46DjGdQAnAMCfVDMECSWvJLwsJgBUFE2Fa1OiicxrgFA1g08Lk6wFqxhjZwV3-Zua0N5O1rjOmfIzaBNcludnB-I70haWbIIHZIrO1jiBnLRTn0iH_0ULZlb3UaSPFn4QffGr3yfI26T1cmv7JhDkotEDy25_nUyZGH92Ovo9NPiUaf7aJ8d1tPiy4f3ny-vy_mnq5vLi3lpaklT2coWJDNocEmXIu81s1ZjxzjHTjZGS1xiS02nmTQoag6aVpVuKjC2bfWSnRbv9rnjtNzY1tghBd2rMbiNDj-U1079eTO4lfrqt6quq4bWuf7NoT74u8nGpDYuGtv3erC5B4qLmiJn9L8QBUcuqcjw9V9w7aeQ-xcVBWQCGsEyOt8jE3yMwXb3L0ZQu8mr3eTVcfK54uXvHz36w6gzeHUAu8pjHFWIqkIKWbz9t1Dd1PfJfk-ZvtjTdUw-3FvGRNUIzn4CXXjNLw</recordid><startdate>20050315</startdate><enddate>20050315</enddate><creator>Xu, Zhenrong</creator><creator>Chen, Linyun</creator><creator>Leung, Laura</creator><creator>T. S. Benedict Yen</creator><creator>Lee, Candy</creator><creator>Chan, Jefferson Y.</creator><creator>Kan, Yuet Wai</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20050315</creationdate><title>Liver-Specific Inactivation of the Nrf1 Gene in Adult Mouse Leads to Nonalcoholic Steatohepatitis and Hepatic Neoplasia</title><author>Xu, Zhenrong ; Chen, Linyun ; Leung, Laura ; T. S. Benedict Yen ; Lee, Candy ; Chan, Jefferson Y. ; Kan, Yuet Wai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-d9d093c1c1b2b7d09a3eea1f3661f98ca91b1d2cfa39c17560a244a840ceddab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Alleles</topic><topic>Animals</topic><topic>Antioxidants - metabolism</topic><topic>Apoptosis</topic><topic>Biological Sciences</topic><topic>Cell growth</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Fatty acids</topic><topic>Fatty Acids - metabolism</topic><topic>Gene expression</topic><topic>Hepatitis - genetics</topic><topic>Hepatitis - metabolism</topic><topic>Hepatocytes</topic><topic>Inflammation</topic><topic>Lipids</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver Neoplasms - etiology</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microsomes, Liver - metabolism</topic><topic>Mutation</topic><topic>Nuclear Respiratory Factor 1</topic><topic>Nuclear Respiratory Factors</topic><topic>Oxidation</topic><topic>Oxidation-Reduction</topic><topic>Oxidative stress</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Response Elements - physiology</topic><topic>Reverse transcriptase polymerase chain reaction</topic><topic>Rodents</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Zhenrong</creatorcontrib><creatorcontrib>Chen, Linyun</creatorcontrib><creatorcontrib>Leung, Laura</creatorcontrib><creatorcontrib>T. S. Benedict Yen</creatorcontrib><creatorcontrib>Lee, Candy</creatorcontrib><creatorcontrib>Chan, Jefferson Y.</creatorcontrib><creatorcontrib>Kan, Yuet Wai</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Zhenrong</au><au>Chen, Linyun</au><au>Leung, Laura</au><au>T. S. Benedict Yen</au><au>Lee, Candy</au><au>Chan, Jefferson Y.</au><au>Kan, Yuet Wai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liver-Specific Inactivation of the Nrf1 Gene in Adult Mouse Leads to Nonalcoholic Steatohepatitis and Hepatic Neoplasia</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2005-03-15</date><risdate>2005</risdate><volume>102</volume><issue>11</issue><spage>4120</spage><epage>4125</epage><pages>4120-4125</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>15738389</pmid><doi>10.1073/pnas.0500660102</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2005-03, Vol.102 (11), p.4120-4125 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_17616927 |
| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Alleles Animals Antioxidants - metabolism Apoptosis Biological Sciences Cell growth DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Fatty acids Fatty Acids - metabolism Gene expression Hepatitis - genetics Hepatitis - metabolism Hepatocytes Inflammation Lipids Liver Liver - metabolism Liver Neoplasms - etiology Liver Neoplasms - genetics Liver Neoplasms - metabolism Mice Mice, Knockout Microsomes, Liver - metabolism Mutation Nuclear Respiratory Factor 1 Nuclear Respiratory Factors Oxidation Oxidation-Reduction Oxidative stress Reactive Oxygen Species - metabolism Response Elements - physiology Reverse transcriptase polymerase chain reaction Rodents Trans-Activators - genetics Trans-Activators - metabolism |
| title | Liver-Specific Inactivation of the Nrf1 Gene in Adult Mouse Leads to Nonalcoholic Steatohepatitis and Hepatic Neoplasia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T23%3A41%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Liver-Specific%20Inactivation%20of%20the%20Nrf1%20Gene%20in%20Adult%20Mouse%20Leads%20to%20Nonalcoholic%20Steatohepatitis%20and%20Hepatic%20Neoplasia&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Xu,%20Zhenrong&rft.date=2005-03-15&rft.volume=102&rft.issue=11&rft.spage=4120&rft.epage=4125&rft.pages=4120-4125&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.0500660102&rft_dat=%3Cjstor_proqu%3E3374876%3C/jstor_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=201370873&rft_id=info:pmid/15738389&rft_jstor_id=3374876&rfr_iscdi=true |