<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>1130-0108</journal-id>
<journal-title><![CDATA[Revista Española de Enfermedades Digestivas]]></journal-title>
<abbrev-journal-title><![CDATA[Rev. esp. enferm. dig.]]></abbrev-journal-title>
<issn>1130-0108</issn>
<publisher>
<publisher-name><![CDATA[Sociedad Española de Patología Digestiva]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S1130-01082018000700004</article-id>
<article-id pub-id-type="doi">10.17235/reed.2018.5004/2017</article-id>
<title-group>
<article-title xml:lang="en"><![CDATA[Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Gil-Gómez]]></surname>
<given-names><![CDATA[Antonio]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Gómez-Sotelo]]></surname>
<given-names><![CDATA[Ana-Isabel]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Ranchal]]></surname>
<given-names><![CDATA[Isidora]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Rojas]]></surname>
<given-names><![CDATA[Ángela]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[García-Valdecasas]]></surname>
<given-names><![CDATA[Marta]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Muñoz-Hernández]]></surname>
<given-names><![CDATA[Rocío]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Gallego-Durán]]></surname>
<given-names><![CDATA[Rocío]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Ampuero]]></surname>
<given-names><![CDATA[Javier]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
<xref ref-type="aff" rid="Aaf"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Romero-Gómez]]></surname>
<given-names><![CDATA[Manuel]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
<xref ref-type="aff" rid="Aaf"/>
</contrib>
</contrib-group>
<aff id="Af1">
<institution><![CDATA[,Universidad de Sevilla. CiberEHD Hospital Universitario Virgen del Rocío/CSIC Instituto de Biomedicina de Sevilla (IBiS)]]></institution>
<addr-line><![CDATA[Sevilla ]]></addr-line>
<country>Spain</country>
</aff>
<aff id="Af2">
<institution><![CDATA[,Hospital Universitario de Valme Unit for Clinical Management of Digestive Diseases ]]></institution>
<addr-line><![CDATA[Sevilla ]]></addr-line>
<country>Spain</country>
</aff>
<aff id="Af3">
<institution><![CDATA[,Hospital Universitario Virgen del Rocío Unit for the Clinical Management of Digestive Diseases ]]></institution>
<addr-line><![CDATA[Sevilla ]]></addr-line>
<country>Spain</country>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>00</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>00</month>
<year>2018</year>
</pub-date>
<volume>110</volume>
<numero>7</numero>
<fpage>427</fpage>
<lpage>433</lpage>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_arttext&amp;pid=S1130-01082018000700004&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_abstract&amp;pid=S1130-01082018000700004&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_pdf&amp;pid=S1130-01082018000700004&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="en"><p><![CDATA[ABSTRACT Aim: to analyze the effect of metformin on ammonia production derived from glutamine metabolism in vitro and in vivo.  Methods:  twenty male Wistar rats were studied for 28 days after a porto-caval anastomosis (n = 16) or a sham operation (n = 4). Porto-caval shunted animals were randomized into two groups (n = 8) and either received 30 mg/kg/day of metformin for two weeks or were control animals. Plasma ammonia concentration, Gls gene expression and K-type glutaminase activity were measured in the small intestine, muscle and kidney. Furthermore, Caco2 were grown in different culture media containing glucose/glutamine as the main carbon source and exposed to different concentrations of the drug. The expression of genes implicated in glutamine metabolism were analyzed.  Results:  metformin was associated with a significant inhibition of glutaminase activity levels in the small intestine of porto-caval shunted rats (0.277 ± 0.07 IU/mg vs 0.142 ± 0.04 IU/mg) and a significant decrease in plasma ammonia (204.3 ± 24.4 µg/dl vs 129.6 ± 16.1 µg/dl). Glucose withdrawal induced the expression of the glutamine transporter SLC1A5 (2.54 ± 0.33 fold change; p &lt; 0.05). Metformin use reduced MYC levels in Caco2 and consequently, SLC1A5 and GLS expression, with a greater effect in cells dependent on glutaminolytic metabolism.  Conclusion:  metformin regulates ammonia homeostasis by modulating glutamine metabolism in the enterocyte, exerting an indirect control of both the uptake and degradation of glutamine. This entails a reduction in the production of metabolites and energy through this pathway and indirectly causes a decrease in ammonia production that could be related to a decreased risk of HE development.]]></p></abstract>
<kwd-group>
<kwd lng="en"><![CDATA[Hepatic encephalopathy]]></kwd>
<kwd lng="en"><![CDATA[Metformin]]></kwd>
<kwd lng="en"><![CDATA[Ammonia]]></kwd>
<kwd lng="en"><![CDATA[Glutaminase]]></kwd>
<kwd lng="en"><![CDATA[Glutamine]]></kwd>
<kwd lng="en"><![CDATA[Cirrhosis]]></kwd>
<kwd lng="en"><![CDATA[ASCT2]]></kwd>
<kwd lng="en"><![CDATA[mTOR]]></kwd>
<kwd lng="en"><![CDATA[Porto-caval anastomosis]]></kwd>
</kwd-group>
</article-meta>
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