Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes
Identifieur interne : 000503 ( Pmc/Curation ); précédent : 000502; suivant : 000504Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes
Auteurs : Kaihui Lu [Allemagne] ; Marcel Zimmermann [Allemagne] ; Boris Görg [Allemagne] ; Hans-Jürgen Bidmon [Allemagne] ; Barbara Biermann [Allemagne] ; Nikolaj Klöcker [Allemagne] ; Dieter H Ussinger [Allemagne] ; Andreas S. Reichert [Allemagne]Source :
- EBioMedicine [ 2352-3964 ] ; 2019.
Abstract
Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients.
Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an
We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an
Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE.
Supported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).
Url:
DOI: 10.1016/j.ebiom.2019.09.058
PubMed: 31648987
PubMed Central: 6838440
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Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>C. & O. Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Biermann, Barbara" sort="Biermann, Barbara" uniqKey="Biermann B" first="Barbara" last="Biermann">Barbara Biermann</name><affiliation wicri:level="1"><nlm:aff id="aff0004">Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Klocker, Nikolaj" sort="Klocker, Nikolaj" uniqKey="Klocker N" first="Nikolaj" last="Klöcker">Nikolaj Klöcker</name><affiliation wicri:level="1"><nlm:aff id="aff0004">Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="H Ussinger, Dieter" sort="H Ussinger, Dieter" uniqKey="H Ussinger D" first="Dieter" last="H Ussinger">Dieter H Ussinger</name><affiliation wicri:level="1"><nlm:aff id="aff0002">Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Reichert, Andreas S" sort="Reichert, Andreas S" uniqKey="Reichert A" first="Andreas S." last="Reichert">Andreas S. Reichert</name><affiliation wicri:level="1"><nlm:aff id="aff0001">Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31648987</idno><idno type="pmc">6838440</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838440</idno><idno type="RBID">PMC:6838440</idno><idno type="doi">10.1016/j.ebiom.2019.09.058</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000503</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000503</idno><idno type="wicri:Area/Pmc/Curation">000503</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000503</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes</title><author><name sortKey="Lu, Kaihui" sort="Lu, Kaihui" uniqKey="Lu K" first="Kaihui" last="Lu">Kaihui Lu</name><affiliation wicri:level="1"><nlm:aff id="aff0001">Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Zimmermann, Marcel" sort="Zimmermann, Marcel" uniqKey="Zimmermann M" first="Marcel" last="Zimmermann">Marcel Zimmermann</name><affiliation wicri:level="1"><nlm:aff id="aff0001">Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Gorg, Boris" sort="Gorg, Boris" uniqKey="Gorg B" first="Boris" last="Görg">Boris Görg</name><affiliation wicri:level="1"><nlm:aff id="aff0002">Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Bidmon, Hans Jurgen" sort="Bidmon, Hans Jurgen" uniqKey="Bidmon H" first="Hans-Jürgen" last="Bidmon">Hans-Jürgen Bidmon</name><affiliation wicri:level="1"><nlm:aff id="aff0003">C. & O. Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>C. & O. Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Biermann, Barbara" sort="Biermann, Barbara" uniqKey="Biermann B" first="Barbara" last="Biermann">Barbara Biermann</name><affiliation wicri:level="1"><nlm:aff id="aff0004">Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Klocker, Nikolaj" sort="Klocker, Nikolaj" uniqKey="Klocker N" first="Nikolaj" last="Klöcker">Nikolaj Klöcker</name><affiliation wicri:level="1"><nlm:aff id="aff0004">Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="H Ussinger, Dieter" sort="H Ussinger, Dieter" uniqKey="H Ussinger D" first="Dieter" last="H Ussinger">Dieter H Ussinger</name><affiliation wicri:level="1"><nlm:aff id="aff0002">Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author><author><name sortKey="Reichert, Andreas S" sort="Reichert, Andreas S" uniqKey="Reichert A" first="Andreas S." last="Reichert">Andreas S. Reichert</name><affiliation wicri:level="1"><nlm:aff id="aff0001">Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf</wicri:regionArea></affiliation></author></analytic><series><title level="j">EBioMedicine</title><idno type="eISSN">2352-3964</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients.</p></sec><sec><title>Methods</title><p>Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an <italic>in vivo</italic> rat HE model, and <italic>post mortem</italic> brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy.</p></sec><sec><title>Findings</title><p>We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an <italic>in vivo</italic> rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of <italic>in vitro-</italic> and <italic>in vivo-</italic>HE models as well as in <italic>post mortem</italic> brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation.</p></sec><sec><title>Interpretation</title><p>Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE.</p></sec><sec><title>Funding</title><p>Supported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="H Ussinger, D" uniqKey="H Ussinger D">D. Häussinger</name></author><author><name sortKey="Sies, H" uniqKey="Sies H">H. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">EBioMedicine</journal-id><journal-id journal-id-type="iso-abbrev">EBioMedicine</journal-id><journal-title-group><journal-title>EBioMedicine</journal-title></journal-title-group><issn pub-type="epub">2352-3964</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31648987</article-id><article-id pub-id-type="pmc">6838440</article-id><article-id pub-id-type="publisher-id">S2352-3964(19)30640-1</article-id><article-id pub-id-type="doi">10.1016/j.ebiom.2019.09.058</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research paper</subject></subj-group></article-categories><title-group><article-title>Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0001"><name><surname>Lu</surname><given-names>Kaihui</given-names></name><xref rid="aff0001" ref-type="aff">a</xref><xref rid="fn1" ref-type="fn">#</xref></contrib><contrib contrib-type="author" id="au0002"><name><surname>Zimmermann</surname><given-names>Marcel</given-names></name><xref rid="aff0001" ref-type="aff">a</xref><xref rid="fn1" ref-type="fn">#</xref></contrib><contrib contrib-type="author" id="au0003"><name><surname>Görg</surname><given-names>Boris</given-names></name><xref rid="aff0002" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0004"><name><surname>Bidmon</surname><given-names>Hans-Jürgen</given-names></name><xref rid="aff0003" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au0005"><name><surname>Biermann</surname><given-names>Barbara</given-names></name><xref rid="aff0004" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au0006"><name><surname>Klöcker</surname><given-names>Nikolaj</given-names></name><xref rid="aff0004" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au0007"><name><surname>Häussinger</surname><given-names>Dieter</given-names></name><xref rid="aff0002" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0008"><name><surname>Reichert</surname><given-names>Andreas S.</given-names></name><email>reichert@hhu.de</email><xref rid="aff0001" ref-type="aff">a</xref><xref rid="cor0001" ref-type="corresp">⁎</xref></contrib></contrib-group><aff id="aff0001"><label>a</label>Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</aff><aff id="aff0002"><label>b</label>Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</aff><aff id="aff0003"><label>c</label>C. & O. Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</aff><aff id="aff0004"><label>d</label>Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany</aff><author-notes><corresp id="cor0001"><label>⁎</label>Corresponding author. <email>reichert@hhu.de</email></corresp><fn id="fn1"><label>#</label><p id="notep0001">These two authors contributed equally</p></fn></author-notes><pub-date pub-type="pmc-release"><day>21</day><month>10</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><month>10</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>21</day><month>10</month><year>2019</year></pub-date><volume>48</volume><fpage>539</fpage><lpage>553</lpage><history><date date-type="received"><day>13</day><month>3</month><year>2019</year></date><date date-type="rev-recd"><day>18</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>19</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 The Author(s). Published by Elsevier B.V.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder></copyright-holder><license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</license-p></license></permissions><abstract id="abs0001"><sec><title>Background</title><p>Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients.</p></sec><sec><title>Methods</title><p>Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an <italic>in vivo</italic> rat HE model, and <italic>post mortem</italic> brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy.</p></sec><sec><title>Findings</title><p>We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an <italic>in vivo</italic> rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of <italic>in vitro-</italic> and <italic>in vivo-</italic>HE models as well as in <italic>post mortem</italic> brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation.</p></sec><sec><title>Interpretation</title><p>Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE.</p></sec><sec><title>Funding</title><p>Supported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).</p></sec></abstract><kwd-group id="keys0001"><title>Keywords</title><kwd>Hepatic encephalopathy</kwd><kwd>Liver disease</kwd><kwd>Autophagy</kwd><kwd>Lysosome</kwd><kwd>Taurine</kwd></kwd-group><kwd-group id="keys0002"><title>Abbreviations</title><kwd>CCCP, carbonyl cyanide m-chlorophenylhydrazone</kwd><kwd>CQ, chloroquine</kwd><kwd>EM, electron microscopy</kwd><kwd>HE, hepatic encephalopathy</kwd><kwd>IF, Immunofluorescence</kwd><kwd>LC3, microtubule-associated protein 1A/1B-light chain 3</kwd><kwd>mQC, mitochondrial quality control</kwd><kwd>MSO, L-methionine-S-sulfoximine</kwd><kwd>NAC, N-acetyl-L-cysteine</kwd><kwd>Rapa, rapamycin</kwd><kwd>ROS, reactive oxygen species</kwd><kwd>TGM2, transglutaminase 2</kwd><kwd>WB, Western Blot</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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