Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans
ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.Desig...
Gespeichert in:
| Veröffentlicht in: | Gut 2021-03, Vol.70 (3), p.585-594 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 594 |
|---|---|
| container_issue | 3 |
| container_start_page | 585 |
| container_title | Gut |
| container_volume | 70 |
| creator | Grander, Christoph Schaefer, Benedikt Schwärzler, Julian Grabherr, Felix de Graaf, Dennis M Enrich, Barbara Oberhuber, Georg Mayr, Lisa Sangineto, Moris Jaschke, Nikolai Adolph, Timon E Effenberger, Maria Moschen, Alexander R Dinarello, Charles A Zoller, Heinz Tilg, Herbert |
| description | ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.DesignAn unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.ResultsCirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.ConclusionCirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis. |
| doi_str_mv | 10.1136/gutjnl-2020-321375 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2426537743</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2426537743</sourcerecordid><originalsourceid>FETCH-LOGICAL-b408t-de341528663e802357d89b7302a7cb2ae48b6bcd51795ab8f7ebebfcda575c9b3</originalsourceid><addsrcrecordid>eNqNkEtLw0AUhQdRbK3-ARcScONm6jwyjyxL8QUFN7oOM8ltmzJJ6kwi9N87JbWCC3E13OE7h8OH0DUlU0q5vF_13aZxmBFGMGeUK3GCxjSVOl5an6IxIVRhodJshC5C2BBCtM7oORpxJrOMZHqMFjO3XRtME9N0Ved321A1yar9BN-ExLiiXbcOe3CmgzJxVfxPyiqACZBEsK4KiMkyWfe1acIlOlsaF-Dq8E7Q--PD2_wZL16fXuazBbYp0R0ugadUMC0lB00YF6rUmVWcMKMKywyk2kpblIKqTBirlwos2GVRGqFEkVk-QXdD79a3Hz2ELq-rUIBzpoG2DzlLmRRcqZRH9PYXuml738R1kYoLhGRKRooNVOHbEDws862vauN3OSX53nU-uM73rvPBdQzdHKp7W0N5jHzLjQAeAFtv_lc4_eGPM_8IfAHSa5hL</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2486656276</pqid></control><display><type>article</type><title>Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans</title><source>MEDLINE</source><source>PubMed Central</source><creator>Grander, Christoph ; Schaefer, Benedikt ; Schwärzler, Julian ; Grabherr, Felix ; de Graaf, Dennis M ; Enrich, Barbara ; Oberhuber, Georg ; Mayr, Lisa ; Sangineto, Moris ; Jaschke, Nikolai ; Adolph, Timon E ; Effenberger, Maria ; Moschen, Alexander R ; Dinarello, Charles A ; Zoller, Heinz ; Tilg, Herbert</creator><creatorcontrib>Grander, Christoph ; Schaefer, Benedikt ; Schwärzler, Julian ; Grabherr, Felix ; de Graaf, Dennis M ; Enrich, Barbara ; Oberhuber, Georg ; Mayr, Lisa ; Sangineto, Moris ; Jaschke, Nikolai ; Adolph, Timon E ; Effenberger, Maria ; Moschen, Alexander R ; Dinarello, Charles A ; Zoller, Heinz ; Tilg, Herbert</creatorcontrib><description>ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.DesignAn unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.ResultsCirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.ConclusionCirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2020-321375</identifier><identifier>PMID: 32699098</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Alcohol ; ALCOHOLIC LIVER DISEASE ; alpha 1-Antitrypsin - genetics ; alpha 1-Antitrypsin - physiology ; Animals ; Cirrhosis ; Clinical medicine ; Clinical trials ; Cytokines ; Cytokines - metabolism ; Disease Models, Animal ; Ethanol ; Experiments ; Fatty liver ; Female ; Genotype ; Hepatitis ; Hepatology ; Humans ; Inflammation ; Laboratories ; Leukocytes (neutrophilic) ; LIVER CIRRHOSIS ; Liver diseases ; Liver Diseases, Alcoholic - genetics ; Liver Diseases, Alcoholic - metabolism ; Liver Diseases, Alcoholic - mortality ; Liver transplantation ; Male ; Medical records ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Neutrophil Infiltration - drug effects ; Pathogenesis ; Patients ; Proteins ; Regression analysis ; Steatosis ; Survival Analysis ; Transplants & implants ; Tumor necrosis factor-TNF</subject><ispartof>Gut, 2021-03, Vol.70 (3), p.585-594</ispartof><rights>Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2021 Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b408t-de341528663e802357d89b7302a7cb2ae48b6bcd51795ab8f7ebebfcda575c9b3</citedby><cites>FETCH-LOGICAL-b408t-de341528663e802357d89b7302a7cb2ae48b6bcd51795ab8f7ebebfcda575c9b3</cites><orcidid>0000-0003-3598-7848 ; 0000-0003-2971-6224 ; 0000-0002-4235-2579</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32699098$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grander, Christoph</creatorcontrib><creatorcontrib>Schaefer, Benedikt</creatorcontrib><creatorcontrib>Schwärzler, Julian</creatorcontrib><creatorcontrib>Grabherr, Felix</creatorcontrib><creatorcontrib>de Graaf, Dennis M</creatorcontrib><creatorcontrib>Enrich, Barbara</creatorcontrib><creatorcontrib>Oberhuber, Georg</creatorcontrib><creatorcontrib>Mayr, Lisa</creatorcontrib><creatorcontrib>Sangineto, Moris</creatorcontrib><creatorcontrib>Jaschke, Nikolai</creatorcontrib><creatorcontrib>Adolph, Timon E</creatorcontrib><creatorcontrib>Effenberger, Maria</creatorcontrib><creatorcontrib>Moschen, Alexander R</creatorcontrib><creatorcontrib>Dinarello, Charles A</creatorcontrib><creatorcontrib>Zoller, Heinz</creatorcontrib><creatorcontrib>Tilg, Herbert</creatorcontrib><title>Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans</title><title>Gut</title><addtitle>Gut</addtitle><addtitle>Gut</addtitle><description>ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.DesignAn unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.ResultsCirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.ConclusionCirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.</description><subject>Alcohol</subject><subject>ALCOHOLIC LIVER DISEASE</subject><subject>alpha 1-Antitrypsin - genetics</subject><subject>alpha 1-Antitrypsin - physiology</subject><subject>Animals</subject><subject>Cirrhosis</subject><subject>Clinical medicine</subject><subject>Clinical trials</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Ethanol</subject><subject>Experiments</subject><subject>Fatty liver</subject><subject>Female</subject><subject>Genotype</subject><subject>Hepatitis</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Laboratories</subject><subject>Leukocytes (neutrophilic)</subject><subject>LIVER CIRRHOSIS</subject><subject>Liver diseases</subject><subject>Liver Diseases, Alcoholic - genetics</subject><subject>Liver Diseases, Alcoholic - metabolism</subject><subject>Liver Diseases, Alcoholic - mortality</subject><subject>Liver transplantation</subject><subject>Male</subject><subject>Medical records</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Middle Aged</subject><subject>Neutrophil Infiltration - drug effects</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Proteins</subject><subject>Regression analysis</subject><subject>Steatosis</subject><subject>Survival Analysis</subject><subject>Transplants & implants</subject><subject>Tumor necrosis factor-TNF</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkEtLw0AUhQdRbK3-ARcScONm6jwyjyxL8QUFN7oOM8ltmzJJ6kwi9N87JbWCC3E13OE7h8OH0DUlU0q5vF_13aZxmBFGMGeUK3GCxjSVOl5an6IxIVRhodJshC5C2BBCtM7oORpxJrOMZHqMFjO3XRtME9N0Ved321A1yar9BN-ExLiiXbcOe3CmgzJxVfxPyiqACZBEsK4KiMkyWfe1acIlOlsaF-Dq8E7Q--PD2_wZL16fXuazBbYp0R0ugadUMC0lB00YF6rUmVWcMKMKywyk2kpblIKqTBirlwos2GVRGqFEkVk-QXdD79a3Hz2ELq-rUIBzpoG2DzlLmRRcqZRH9PYXuml738R1kYoLhGRKRooNVOHbEDws862vauN3OSX53nU-uM73rvPBdQzdHKp7W0N5jHzLjQAeAFtv_lc4_eGPM_8IfAHSa5hL</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Grander, Christoph</creator><creator>Schaefer, Benedikt</creator><creator>Schwärzler, Julian</creator><creator>Grabherr, Felix</creator><creator>de Graaf, Dennis M</creator><creator>Enrich, Barbara</creator><creator>Oberhuber, Georg</creator><creator>Mayr, Lisa</creator><creator>Sangineto, Moris</creator><creator>Jaschke, Nikolai</creator><creator>Adolph, Timon E</creator><creator>Effenberger, Maria</creator><creator>Moschen, Alexander R</creator><creator>Dinarello, Charles A</creator><creator>Zoller, Heinz</creator><creator>Tilg, Herbert</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ Publishing Group LTD</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3598-7848</orcidid><orcidid>https://orcid.org/0000-0003-2971-6224</orcidid><orcidid>https://orcid.org/0000-0002-4235-2579</orcidid></search><sort><creationdate>20210301</creationdate><title>Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans</title><author>Grander, Christoph ; Schaefer, Benedikt ; Schwärzler, Julian ; Grabherr, Felix ; de Graaf, Dennis M ; Enrich, Barbara ; Oberhuber, Georg ; Mayr, Lisa ; Sangineto, Moris ; Jaschke, Nikolai ; Adolph, Timon E ; Effenberger, Maria ; Moschen, Alexander R ; Dinarello, Charles A ; Zoller, Heinz ; Tilg, Herbert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b408t-de341528663e802357d89b7302a7cb2ae48b6bcd51795ab8f7ebebfcda575c9b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alcohol</topic><topic>ALCOHOLIC LIVER DISEASE</topic><topic>alpha 1-Antitrypsin - genetics</topic><topic>alpha 1-Antitrypsin - physiology</topic><topic>Animals</topic><topic>Cirrhosis</topic><topic>Clinical medicine</topic><topic>Clinical trials</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Ethanol</topic><topic>Experiments</topic><topic>Fatty liver</topic><topic>Female</topic><topic>Genotype</topic><topic>Hepatitis</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Laboratories</topic><topic>Leukocytes (neutrophilic)</topic><topic>LIVER CIRRHOSIS</topic><topic>Liver diseases</topic><topic>Liver Diseases, Alcoholic - genetics</topic><topic>Liver Diseases, Alcoholic - metabolism</topic><topic>Liver Diseases, Alcoholic - mortality</topic><topic>Liver transplantation</topic><topic>Male</topic><topic>Medical records</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Middle Aged</topic><topic>Neutrophil Infiltration - drug effects</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Proteins</topic><topic>Regression analysis</topic><topic>Steatosis</topic><topic>Survival Analysis</topic><topic>Transplants & implants</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grander, Christoph</creatorcontrib><creatorcontrib>Schaefer, Benedikt</creatorcontrib><creatorcontrib>Schwärzler, Julian</creatorcontrib><creatorcontrib>Grabherr, Felix</creatorcontrib><creatorcontrib>de Graaf, Dennis M</creatorcontrib><creatorcontrib>Enrich, Barbara</creatorcontrib><creatorcontrib>Oberhuber, Georg</creatorcontrib><creatorcontrib>Mayr, Lisa</creatorcontrib><creatorcontrib>Sangineto, Moris</creatorcontrib><creatorcontrib>Jaschke, Nikolai</creatorcontrib><creatorcontrib>Adolph, Timon E</creatorcontrib><creatorcontrib>Effenberger, Maria</creatorcontrib><creatorcontrib>Moschen, Alexander R</creatorcontrib><creatorcontrib>Dinarello, Charles A</creatorcontrib><creatorcontrib>Zoller, Heinz</creatorcontrib><creatorcontrib>Tilg, Herbert</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grander, Christoph</au><au>Schaefer, Benedikt</au><au>Schwärzler, Julian</au><au>Grabherr, Felix</au><au>de Graaf, Dennis M</au><au>Enrich, Barbara</au><au>Oberhuber, Georg</au><au>Mayr, Lisa</au><au>Sangineto, Moris</au><au>Jaschke, Nikolai</au><au>Adolph, Timon E</au><au>Effenberger, Maria</au><au>Moschen, Alexander R</au><au>Dinarello, Charles A</au><au>Zoller, Heinz</au><au>Tilg, Herbert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans</atitle><jtitle>Gut</jtitle><stitle>Gut</stitle><addtitle>Gut</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>70</volume><issue>3</issue><spage>585</spage><epage>594</epage><pages>585-594</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><abstract>ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.DesignAn unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.ResultsCirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.ConclusionCirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><pmid>32699098</pmid><doi>10.1136/gutjnl-2020-321375</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3598-7848</orcidid><orcidid>https://orcid.org/0000-0003-2971-6224</orcidid><orcidid>https://orcid.org/0000-0002-4235-2579</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0017-5749 |
| ispartof | Gut, 2021-03, Vol.70 (3), p.585-594 |
| issn | 0017-5749 1468-3288 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2426537743 |
| source | MEDLINE; PubMed Central |
| subjects | Alcohol ALCOHOLIC LIVER DISEASE alpha 1-Antitrypsin - genetics alpha 1-Antitrypsin - physiology Animals Cirrhosis Clinical medicine Clinical trials Cytokines Cytokines - metabolism Disease Models, Animal Ethanol Experiments Fatty liver Female Genotype Hepatitis Hepatology Humans Inflammation Laboratories Leukocytes (neutrophilic) LIVER CIRRHOSIS Liver diseases Liver Diseases, Alcoholic - genetics Liver Diseases, Alcoholic - metabolism Liver Diseases, Alcoholic - mortality Liver transplantation Male Medical records Mice Mice, Inbred C57BL Mice, Transgenic Middle Aged Neutrophil Infiltration - drug effects Pathogenesis Patients Proteins Regression analysis Steatosis Survival Analysis Transplants & implants Tumor necrosis factor-TNF |
| title | Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T08%3A37%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Alpha-1%20antitrypsin%20governs%20alcohol-related%20liver%20disease%20in%20mice%20and%20humans&rft.jtitle=Gut&rft.au=Grander,%20Christoph&rft.date=2021-03-01&rft.volume=70&rft.issue=3&rft.spage=585&rft.epage=594&rft.pages=585-594&rft.issn=0017-5749&rft.eissn=1468-3288&rft_id=info:doi/10.1136/gutjnl-2020-321375&rft_dat=%3Cproquest_cross%3E2426537743%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2486656276&rft_id=info:pmid/32699098&rfr_iscdi=true |