title: Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice.
abstract: OBJECTIVE
  Bile acids (BA) are increasingly recognized as important modulators of liver regeneration. Increased enterohepatic BA flux has been proposed to generate specific signals that activate hepatocyte proliferation after partial hepatectomy (PH). We have investigated the role of the BA membrane transporter Mrp3 (Abcc3), which is expressed in the liver and gut, in the hepatic growth response elicited by BA and in liver regeneration after PH.
  
  
  METHODS
  Liver growth and regeneration, and the expression of growth-related genes, were studied in Mrp3(+/+) and Mrp3(-/-) mice fed a cholic acid (CA) supplemented diet and after 2/3 PH. Activation of the BA receptor FXR was measured in mice after in vivo transduction of the liver with a FXR-Luciferase reporter plasmid. BA levels were measured in portal serum and liver tissue by high performance liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  Liver growth elicited by CA feeding was significantly reduced in Mrp3(-/-) mice. These animals showed reduced FXR activation in the liver after CA administration and decreased portal serum levels of BA. Liver regeneration after PH was significantly delayed in Mrp3-deficient mice. Proliferation-related gene expression and peak DNA synthesis in Mrp3(-/-) mice occurred later than in wild types, coinciding with a retarded elevation in intra-hepatic BA levels.
  
  
  CONCLUSIONS
  Lack of Abcc3 expression markedly impairs liver growth in response to BA and after PH. Our data suggest that Mrp3 plays a non-redundant role in the regulation of BA flux during liver regeneration.
authors.affiliation: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernández-Barrena
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Monte
authors.forename: Maria U
authors.initials: MU
authors.lastname: Latasa
authors.forename: Iker
authors.initials: I
authors.lastname: Uriarte
authors.forename: Eva
authors.initials: E
authors.lastname: Vicente
authors.forename: Haisul C Y
authors.initials: HC
authors.lastname: Chang
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Rodriguez-Ortigosa
authors.forename: Ronald Oude
authors.initials: RO
authors.lastname: Elferink
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Matias A
authors.initials: MA
authors.lastname: Ávila
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001693:Biological Transport, Active; D019826:Cholic Acid / Q000008:administration & dosage / Q000378:metabolism; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency* / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D019826:Cholic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C114462:multidrug resistance-associated protein 3