Loss of hepatic Mboat7 leads to liver fibrosis
ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mech...
Gespeichert in:
| Veröffentlicht in: | Gut 2021-05, Vol.70 (5), p.940-950 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 950 |
|---|---|
| container_issue | 5 |
| container_start_page | 940 |
| container_title | Gut |
| container_volume | 70 |
| creator | Thangapandi, Veera Raghavan Knittelfelder, Oskar Brosch, Mario Patsenker, Eleonora Vvedenskaya, Olga Buch, Stephan Hinz, Sebastian Hendricks, Alexander Nati, Marina Herrmann, Alexander Rekhade, Devavrat Ravindra Berg, Thomas Matz-Soja, Madlen Huse, Klaus Klipp, Edda Pauling, Josch K Wodke, Judith AH Miranda Ackerman, Jacobo Bonin, Malte von Aigner, Elmar Datz, Christian von Schönfels, Witigo Nehring, Sophie Zeissig, Sebastian Röcken, Christoph Dahl, Andreas Chavakis, Triantafyllos Stickel, Felix Shevchenko, Andrej Schafmayer, Clemens Hampe, Jochen Subramanian, Pallavi |
| description | ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p |
| doi_str_mv | 10.1136/gutjnl-2020-320853 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8040158</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2509485307</sourcerecordid><originalsourceid>FETCH-LOGICAL-b573t-aac67b04d617fa0ce4272a9778fbf018bd3ace506ef7a7304ede913c6646976e3</originalsourceid><addsrcrecordid>eNqNkUtLxDAUhYMozvj4Ay6k4MZNx5tHk3QjyOALRtzoOqRtOpPSacamHfDfm6Hj-FiIq3DJdw73noPQGYYJxpRfzfuuauqYAIGYEpAJ3UNjzLgMk5T7aAyARZwIlo7QkfcVAEiZ4kM0oiRJMaNsjCYz533kymhhVrqzefSUOd2JqDa68FHnotquTRuVNmudt_4EHZS69uZ0-x6j17vbl-lDPHu-f5zezOIsEbSLtc65yIAVHItSQ24YEUSnQsgyKwHLrKA6NwlwUwotKDBTmBTTnHPGU8ENPUbXg--qz5amyE3TtbpWq9YudfuunLbq509jF2ru1koCA5zIYHC5NWjdW298p5bW56audWNc7xVhWGIiKE8CevELrVzfNuE8RRJIWcgVRKDIQOUhCN-acrcMBrWpQw11qE0daqgjiM6_n7GTfOYfgHgAsmX1P8PJF79b8w_BB5GDo5g</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2509485307</pqid></control><display><type>article</type><title>Loss of hepatic Mboat7 leads to liver fibrosis</title><source>MEDLINE</source><source>PubMed Central</source><creator>Thangapandi, Veera Raghavan ; Knittelfelder, Oskar ; Brosch, Mario ; Patsenker, Eleonora ; Vvedenskaya, Olga ; Buch, Stephan ; Hinz, Sebastian ; Hendricks, Alexander ; Nati, Marina ; Herrmann, Alexander ; Rekhade, Devavrat Ravindra ; Berg, Thomas ; Matz-Soja, Madlen ; Huse, Klaus ; Klipp, Edda ; Pauling, Josch K ; Wodke, Judith AH ; Miranda Ackerman, Jacobo ; Bonin, Malte von ; Aigner, Elmar ; Datz, Christian ; von Schönfels, Witigo ; Nehring, Sophie ; Zeissig, Sebastian ; Röcken, Christoph ; Dahl, Andreas ; Chavakis, Triantafyllos ; Stickel, Felix ; Shevchenko, Andrej ; Schafmayer, Clemens ; Hampe, Jochen ; Subramanian, Pallavi</creator><creatorcontrib>Thangapandi, Veera Raghavan ; Knittelfelder, Oskar ; Brosch, Mario ; Patsenker, Eleonora ; Vvedenskaya, Olga ; Buch, Stephan ; Hinz, Sebastian ; Hendricks, Alexander ; Nati, Marina ; Herrmann, Alexander ; Rekhade, Devavrat Ravindra ; Berg, Thomas ; Matz-Soja, Madlen ; Huse, Klaus ; Klipp, Edda ; Pauling, Josch K ; Wodke, Judith AH ; Miranda Ackerman, Jacobo ; Bonin, Malte von ; Aigner, Elmar ; Datz, Christian ; von Schönfels, Witigo ; Nehring, Sophie ; Zeissig, Sebastian ; Röcken, Christoph ; Dahl, Andreas ; Chavakis, Triantafyllos ; Stickel, Felix ; Shevchenko, Andrej ; Schafmayer, Clemens ; Hampe, Jochen ; Subramanian, Pallavi</creatorcontrib><description>ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2020-320853</identifier><identifier>PMID: 32591434</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Acyltransferase ; Acyltransferases - deficiency ; Acyltransferases - genetics ; Adult ; Aged ; Animals ; Biopsy ; Cholesterol ; Choline ; Diet ; Disease Models, Animal ; Disease Progression ; Fatty liver ; Female ; Fibrosis ; Flow cytometry ; Gastrointestinal surgery ; Genotype ; Genotypes ; Haplotypes ; Health risk assessment ; Hepatitis ; Hepatitis B ; Hepatology ; High fat diet ; Histology ; Humans ; Hydroxyproline ; Inflammation ; Inflammation - genetics ; Insulin resistance ; Lipids ; Liver Cirrhosis - genetics ; Liver diseases ; liver fibrosis, lipidomics ; Low fat diet ; Male ; Membrane Proteins - deficiency ; Membrane Proteins - genetics ; Methionine ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Mutation ; NAFLD ; NASH ; Non-alcoholic Fatty Liver Disease - genetics ; Nutrient deficiency ; Phosphatidylinositol ; Polymorphism, Single Nucleotide ; Proteins ; Signal transduction ; Steatosis ; Transcription ; Transcriptomics</subject><ispartof>Gut, 2021-05, Vol.70 (5), p.940-950</ispartof><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2021 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b573t-aac67b04d617fa0ce4272a9778fbf018bd3ace506ef7a7304ede913c6646976e3</citedby><cites>FETCH-LOGICAL-b573t-aac67b04d617fa0ce4272a9778fbf018bd3ace506ef7a7304ede913c6646976e3</cites><orcidid>0000-0002-2421-6127 ; 0000-0002-1565-7238 ; 0000-0002-7286-9245 ; 0000-0002-5079-1109 ; 0000-0002-6989-8002 ; 0000-0001-7838-4532</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040158/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040158/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32591434$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thangapandi, Veera Raghavan</creatorcontrib><creatorcontrib>Knittelfelder, Oskar</creatorcontrib><creatorcontrib>Brosch, Mario</creatorcontrib><creatorcontrib>Patsenker, Eleonora</creatorcontrib><creatorcontrib>Vvedenskaya, Olga</creatorcontrib><creatorcontrib>Buch, Stephan</creatorcontrib><creatorcontrib>Hinz, Sebastian</creatorcontrib><creatorcontrib>Hendricks, Alexander</creatorcontrib><creatorcontrib>Nati, Marina</creatorcontrib><creatorcontrib>Herrmann, Alexander</creatorcontrib><creatorcontrib>Rekhade, Devavrat Ravindra</creatorcontrib><creatorcontrib>Berg, Thomas</creatorcontrib><creatorcontrib>Matz-Soja, Madlen</creatorcontrib><creatorcontrib>Huse, Klaus</creatorcontrib><creatorcontrib>Klipp, Edda</creatorcontrib><creatorcontrib>Pauling, Josch K</creatorcontrib><creatorcontrib>Wodke, Judith AH</creatorcontrib><creatorcontrib>Miranda Ackerman, Jacobo</creatorcontrib><creatorcontrib>Bonin, Malte von</creatorcontrib><creatorcontrib>Aigner, Elmar</creatorcontrib><creatorcontrib>Datz, Christian</creatorcontrib><creatorcontrib>von Schönfels, Witigo</creatorcontrib><creatorcontrib>Nehring, Sophie</creatorcontrib><creatorcontrib>Zeissig, Sebastian</creatorcontrib><creatorcontrib>Röcken, Christoph</creatorcontrib><creatorcontrib>Dahl, Andreas</creatorcontrib><creatorcontrib>Chavakis, Triantafyllos</creatorcontrib><creatorcontrib>Stickel, Felix</creatorcontrib><creatorcontrib>Shevchenko, Andrej</creatorcontrib><creatorcontrib>Schafmayer, Clemens</creatorcontrib><creatorcontrib>Hampe, Jochen</creatorcontrib><creatorcontrib>Subramanian, Pallavi</creatorcontrib><title>Loss of hepatic Mboat7 leads to liver fibrosis</title><title>Gut</title><addtitle>Gut</addtitle><addtitle>Gut</addtitle><description>ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.</description><subject>Acyltransferase</subject><subject>Acyltransferases - deficiency</subject><subject>Acyltransferases - genetics</subject><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Biopsy</subject><subject>Cholesterol</subject><subject>Choline</subject><subject>Diet</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Fatty liver</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Flow cytometry</subject><subject>Gastrointestinal surgery</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Haplotypes</subject><subject>Health risk assessment</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatology</subject><subject>High fat diet</subject><subject>Histology</subject><subject>Humans</subject><subject>Hydroxyproline</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Insulin resistance</subject><subject>Lipids</subject><subject>Liver Cirrhosis - genetics</subject><subject>Liver diseases</subject><subject>liver fibrosis, lipidomics</subject><subject>Low fat diet</subject><subject>Male</subject><subject>Membrane Proteins - deficiency</subject><subject>Membrane Proteins - genetics</subject><subject>Methionine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>NAFLD</subject><subject>NASH</subject><subject>Non-alcoholic Fatty Liver Disease - genetics</subject><subject>Nutrient deficiency</subject><subject>Phosphatidylinositol</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Steatosis</subject><subject>Transcription</subject><subject>Transcriptomics</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkUtLxDAUhYMozvj4Ay6k4MZNx5tHk3QjyOALRtzoOqRtOpPSacamHfDfm6Hj-FiIq3DJdw73noPQGYYJxpRfzfuuauqYAIGYEpAJ3UNjzLgMk5T7aAyARZwIlo7QkfcVAEiZ4kM0oiRJMaNsjCYz533kymhhVrqzefSUOd2JqDa68FHnotquTRuVNmudt_4EHZS69uZ0-x6j17vbl-lDPHu-f5zezOIsEbSLtc65yIAVHItSQ24YEUSnQsgyKwHLrKA6NwlwUwotKDBTmBTTnHPGU8ENPUbXg--qz5amyE3TtbpWq9YudfuunLbq509jF2ru1koCA5zIYHC5NWjdW298p5bW56audWNc7xVhWGIiKE8CevELrVzfNuE8RRJIWcgVRKDIQOUhCN-acrcMBrWpQw11qE0daqgjiM6_n7GTfOYfgHgAsmX1P8PJF79b8w_BB5GDo5g</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Thangapandi, Veera Raghavan</creator><creator>Knittelfelder, Oskar</creator><creator>Brosch, Mario</creator><creator>Patsenker, Eleonora</creator><creator>Vvedenskaya, Olga</creator><creator>Buch, Stephan</creator><creator>Hinz, Sebastian</creator><creator>Hendricks, Alexander</creator><creator>Nati, Marina</creator><creator>Herrmann, Alexander</creator><creator>Rekhade, Devavrat Ravindra</creator><creator>Berg, Thomas</creator><creator>Matz-Soja, Madlen</creator><creator>Huse, Klaus</creator><creator>Klipp, Edda</creator><creator>Pauling, Josch K</creator><creator>Wodke, Judith AH</creator><creator>Miranda Ackerman, Jacobo</creator><creator>Bonin, Malte von</creator><creator>Aigner, Elmar</creator><creator>Datz, Christian</creator><creator>von Schönfels, Witigo</creator><creator>Nehring, Sophie</creator><creator>Zeissig, Sebastian</creator><creator>Röcken, Christoph</creator><creator>Dahl, Andreas</creator><creator>Chavakis, Triantafyllos</creator><creator>Stickel, Felix</creator><creator>Shevchenko, Andrej</creator><creator>Schafmayer, Clemens</creator><creator>Hampe, Jochen</creator><creator>Subramanian, Pallavi</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</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>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>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-2421-6127</orcidid><orcidid>https://orcid.org/0000-0002-1565-7238</orcidid><orcidid>https://orcid.org/0000-0002-7286-9245</orcidid><orcidid>https://orcid.org/0000-0002-5079-1109</orcidid><orcidid>https://orcid.org/0000-0002-6989-8002</orcidid><orcidid>https://orcid.org/0000-0001-7838-4532</orcidid></search><sort><creationdate>20210501</creationdate><title>Loss of hepatic Mboat7 leads to liver fibrosis</title><author>Thangapandi, Veera Raghavan ; Knittelfelder, Oskar ; Brosch, Mario ; Patsenker, Eleonora ; Vvedenskaya, Olga ; Buch, Stephan ; Hinz, Sebastian ; Hendricks, Alexander ; Nati, Marina ; Herrmann, Alexander ; Rekhade, Devavrat Ravindra ; Berg, Thomas ; Matz-Soja, Madlen ; Huse, Klaus ; Klipp, Edda ; Pauling, Josch K ; Wodke, Judith AH ; Miranda Ackerman, Jacobo ; Bonin, Malte von ; Aigner, Elmar ; Datz, Christian ; von Schönfels, Witigo ; Nehring, Sophie ; Zeissig, Sebastian ; Röcken, Christoph ; Dahl, Andreas ; Chavakis, Triantafyllos ; Stickel, Felix ; Shevchenko, Andrej ; Schafmayer, Clemens ; Hampe, Jochen ; Subramanian, Pallavi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b573t-aac67b04d617fa0ce4272a9778fbf018bd3ace506ef7a7304ede913c6646976e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acyltransferase</topic><topic>Acyltransferases - deficiency</topic><topic>Acyltransferases - genetics</topic><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Biopsy</topic><topic>Cholesterol</topic><topic>Choline</topic><topic>Diet</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Fatty liver</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Flow cytometry</topic><topic>Gastrointestinal surgery</topic><topic>Genotype</topic><topic>Genotypes</topic><topic>Haplotypes</topic><topic>Health risk assessment</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatology</topic><topic>High fat diet</topic><topic>Histology</topic><topic>Humans</topic><topic>Hydroxyproline</topic><topic>Inflammation</topic><topic>Inflammation - genetics</topic><topic>Insulin resistance</topic><topic>Lipids</topic><topic>Liver Cirrhosis - genetics</topic><topic>Liver diseases</topic><topic>liver fibrosis, lipidomics</topic><topic>Low fat diet</topic><topic>Male</topic><topic>Membrane Proteins - deficiency</topic><topic>Membrane Proteins - genetics</topic><topic>Methionine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>NAFLD</topic><topic>NASH</topic><topic>Non-alcoholic Fatty Liver Disease - genetics</topic><topic>Nutrient deficiency</topic><topic>Phosphatidylinositol</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Steatosis</topic><topic>Transcription</topic><topic>Transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thangapandi, Veera Raghavan</creatorcontrib><creatorcontrib>Knittelfelder, Oskar</creatorcontrib><creatorcontrib>Brosch, Mario</creatorcontrib><creatorcontrib>Patsenker, Eleonora</creatorcontrib><creatorcontrib>Vvedenskaya, Olga</creatorcontrib><creatorcontrib>Buch, Stephan</creatorcontrib><creatorcontrib>Hinz, Sebastian</creatorcontrib><creatorcontrib>Hendricks, Alexander</creatorcontrib><creatorcontrib>Nati, Marina</creatorcontrib><creatorcontrib>Herrmann, Alexander</creatorcontrib><creatorcontrib>Rekhade, Devavrat Ravindra</creatorcontrib><creatorcontrib>Berg, Thomas</creatorcontrib><creatorcontrib>Matz-Soja, Madlen</creatorcontrib><creatorcontrib>Huse, Klaus</creatorcontrib><creatorcontrib>Klipp, Edda</creatorcontrib><creatorcontrib>Pauling, Josch K</creatorcontrib><creatorcontrib>Wodke, Judith AH</creatorcontrib><creatorcontrib>Miranda Ackerman, Jacobo</creatorcontrib><creatorcontrib>Bonin, Malte von</creatorcontrib><creatorcontrib>Aigner, Elmar</creatorcontrib><creatorcontrib>Datz, Christian</creatorcontrib><creatorcontrib>von Schönfels, Witigo</creatorcontrib><creatorcontrib>Nehring, Sophie</creatorcontrib><creatorcontrib>Zeissig, Sebastian</creatorcontrib><creatorcontrib>Röcken, Christoph</creatorcontrib><creatorcontrib>Dahl, Andreas</creatorcontrib><creatorcontrib>Chavakis, Triantafyllos</creatorcontrib><creatorcontrib>Stickel, Felix</creatorcontrib><creatorcontrib>Shevchenko, Andrej</creatorcontrib><creatorcontrib>Schafmayer, Clemens</creatorcontrib><creatorcontrib>Hampe, Jochen</creatorcontrib><creatorcontrib>Subramanian, Pallavi</creatorcontrib><collection>BMJ Open Access Journals</collection><collection>BMJ Journals:Open Access</collection><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 Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thangapandi, Veera Raghavan</au><au>Knittelfelder, Oskar</au><au>Brosch, Mario</au><au>Patsenker, Eleonora</au><au>Vvedenskaya, Olga</au><au>Buch, Stephan</au><au>Hinz, Sebastian</au><au>Hendricks, Alexander</au><au>Nati, Marina</au><au>Herrmann, Alexander</au><au>Rekhade, Devavrat Ravindra</au><au>Berg, Thomas</au><au>Matz-Soja, Madlen</au><au>Huse, Klaus</au><au>Klipp, Edda</au><au>Pauling, Josch K</au><au>Wodke, Judith AH</au><au>Miranda Ackerman, Jacobo</au><au>Bonin, Malte von</au><au>Aigner, Elmar</au><au>Datz, Christian</au><au>von Schönfels, Witigo</au><au>Nehring, Sophie</au><au>Zeissig, Sebastian</au><au>Röcken, Christoph</au><au>Dahl, Andreas</au><au>Chavakis, Triantafyllos</au><au>Stickel, Felix</au><au>Shevchenko, Andrej</au><au>Schafmayer, Clemens</au><au>Hampe, Jochen</au><au>Subramanian, Pallavi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of hepatic Mboat7 leads to liver fibrosis</atitle><jtitle>Gut</jtitle><stitle>Gut</stitle><addtitle>Gut</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>70</volume><issue>5</issue><spage>940</spage><epage>950</epage><pages>940-950</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><abstract>ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><pmid>32591434</pmid><doi>10.1136/gutjnl-2020-320853</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-2421-6127</orcidid><orcidid>https://orcid.org/0000-0002-1565-7238</orcidid><orcidid>https://orcid.org/0000-0002-7286-9245</orcidid><orcidid>https://orcid.org/0000-0002-5079-1109</orcidid><orcidid>https://orcid.org/0000-0002-6989-8002</orcidid><orcidid>https://orcid.org/0000-0001-7838-4532</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0017-5749 |
| ispartof | Gut, 2021-05, Vol.70 (5), p.940-950 |
| issn | 0017-5749 1468-3288 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8040158 |
| source | MEDLINE; PubMed Central |
| subjects | Acyltransferase Acyltransferases - deficiency Acyltransferases - genetics Adult Aged Animals Biopsy Cholesterol Choline Diet Disease Models, Animal Disease Progression Fatty liver Female Fibrosis Flow cytometry Gastrointestinal surgery Genotype Genotypes Haplotypes Health risk assessment Hepatitis Hepatitis B Hepatology High fat diet Histology Humans Hydroxyproline Inflammation Inflammation - genetics Insulin resistance Lipids Liver Cirrhosis - genetics Liver diseases liver fibrosis, lipidomics Low fat diet Male Membrane Proteins - deficiency Membrane Proteins - genetics Methionine Mice Mice, Inbred C57BL Middle Aged Mutation NAFLD NASH Non-alcoholic Fatty Liver Disease - genetics Nutrient deficiency Phosphatidylinositol Polymorphism, Single Nucleotide Proteins Signal transduction Steatosis Transcription Transcriptomics |
| title | Loss of hepatic Mboat7 leads to liver fibrosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T08%3A25%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Loss%20of%20hepatic%20Mboat7%20leads%20to%20liver%20fibrosis&rft.jtitle=Gut&rft.au=Thangapandi,%20Veera%20Raghavan&rft.date=2021-05-01&rft.volume=70&rft.issue=5&rft.spage=940&rft.epage=950&rft.pages=940-950&rft.issn=0017-5749&rft.eissn=1468-3288&rft_id=info:doi/10.1136/gutjnl-2020-320853&rft_dat=%3Cproquest_pubme%3E2509485307%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2509485307&rft_id=info:pmid/32591434&rfr_iscdi=true |