Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2003-5-12
pubmed:abstractText
Taurolithocholic acid (TLCA) is a potent cholestatic agent. Our recent work suggested that TLCA impairs hepatobiliary exocytosis, insertion of transport proteins into apical hepatocyte membranes, and bile flow by protein kinase Cepsilon (PKCepsilon)-dependent mechanisms. Products of phosphatidylinositol 3-kinases (PI3K) stimulate PKCepsilon. We studied the role of PI3K for TLCA-induced cholestasis in isolated perfused rat liver (IPRL) and isolated rat hepatocyte couplets (IRHC). In IPRL, TLCA (10 micromol/liter) impaired bile flow by 51%, biliary secretion of horseradish peroxidase, a marker of vesicular exocytosis, by 46%, and the Mrp2 substrate, 2,4-dinitrophenyl-S-glutathione, by 95% and stimulated PI3K-dependent protein kinase B, a marker of PI3K activity, by 154% and PKCepsilon membrane binding by 23%. In IRHC, TLCA (2.5 micromol/liter) impaired canalicular secretion of the fluorescent bile acid, cholylglycylamido fluorescein, by 50%. The selective PI3K inhibitor, wortmannin (100 nmol/liter), and the anticholestatic bile acid tauroursodeoxycholic acid (TUDCA, 25 micromol/liter) independently and additively reversed the effects of TLCA on bile flow, exocytosis, organic anion secretion, PI3K-dependent protein kinase B activity, and PKCepsilon membrane binding in IPRL. Wortmannin also reversed impaired bile acid secretion in IRHC. These data strongly suggest that TLCA exerts cholestatic effects by PI3K- and PKCepsilon-dependent mechanisms that are reversed by tauroursodeoxycholic acid in a PI3K-independent way.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Androstadienes, http://linkedlifedata.com/resource/pubmed/chemical/Anions, http://linkedlifedata.com/resource/pubmed/chemical/Bile Acids and Salts, http://linkedlifedata.com/resource/pubmed/chemical/Cholagogues and Choleretics, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Horseradish Peroxidase, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt, http://linkedlifedata.com/resource/pubmed/chemical/Taurochenodeoxycholic Acid, http://linkedlifedata.com/resource/pubmed/chemical/Taurolithocholic Acid, http://linkedlifedata.com/resource/pubmed/chemical/tauroursodeoxycholic acid, http://linkedlifedata.com/resource/pubmed/chemical/wortmannin
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
17810-8
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12626520-Androstadienes, pubmed-meshheading:12626520-Animals, pubmed-meshheading:12626520-Anions, pubmed-meshheading:12626520-Bile Acids and Salts, pubmed-meshheading:12626520-Cell Membrane, pubmed-meshheading:12626520-Cholagogues and Choleretics, pubmed-meshheading:12626520-Enzyme Activation, pubmed-meshheading:12626520-Enzyme Inhibitors, pubmed-meshheading:12626520-Exocytosis, pubmed-meshheading:12626520-Hepatocytes, pubmed-meshheading:12626520-Horseradish Peroxidase, pubmed-meshheading:12626520-Kinetics, pubmed-meshheading:12626520-Liver, pubmed-meshheading:12626520-Male, pubmed-meshheading:12626520-Perfusion, pubmed-meshheading:12626520-Phosphatidylinositol 3-Kinases, pubmed-meshheading:12626520-Precipitin Tests, pubmed-meshheading:12626520-Protein Binding, pubmed-meshheading:12626520-Protein Transport, pubmed-meshheading:12626520-Protein-Serine-Threonine Kinases, pubmed-meshheading:12626520-Proto-Oncogene Proteins, pubmed-meshheading:12626520-Proto-Oncogene Proteins c-akt, pubmed-meshheading:12626520-Rats, pubmed-meshheading:12626520-Rats, Sprague-Dawley, pubmed-meshheading:12626520-Taurochenodeoxycholic Acid, pubmed-meshheading:12626520-Taurolithocholic Acid, pubmed-meshheading:12626520-Time Factors
pubmed:year
2003
pubmed:articleTitle
Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol 3-kinase-dependent mechanisms in perfused rat livers and rat hepatocyte couplets.
pubmed:affiliation
Department of Medicine II-Grosshadern, Klinikum of the University of Munich, 81377 Munich, Germany. beuers@med2.med.uni-muenchen.de
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't