title: Protoporphyrin retention in hepatocytes and Kupffer cells prevents sclerosing cholangitis in erythropoietic protoporphyria mouse model.
abstract: OBJECTIVE
  Chronic, progressive hepatobiliary disease is the most severe complication of erythropoietic protoporphyria (EPP) and can require liver transplantation, although the mechanisms that lead to liver failure are unknown. We characterized protoporphyrin-IX (PPIX)-linked hepatobiliary disease in BALB/c and C57BL/6 (Fechm1Pas) mice with mutations in ferrochelatase as models for EPP.
  
  
  METHODS
  Fechm1Pas and wild-type (control) mice were studied at 12-14 weeks of age. PPIX was quantified; its distribution in the liver, serum levels of lipoprotein-X, liver histology, contents of bile salt and cholesterol phospholipids, and expression of genes were compared in mice of the BALB/c and C57BL/6 backgrounds. The in vitro binding affinity of PPIX for bile components was determined.
  
  
  RESULTS
  Compared with mice of the C57BL/6 background, BALB/c Fechm1Pas mice had a more severe pattern of cholestasis, fibrosis with portoportal bridging, bile acid regurgitation, sclerosing cholangitis, and hepatolithiasis. In C57BL/6 Fechm1Pas mice, PPIX was sequestrated mainly in the cytosol of hepatocytes and Kupffer cells, whereas, in BALB/c Fechm1Pas mice, PPIX was localized within enlarged bile canaliculi. Livers of C57BL/6 Fechm1Pas mice were protected through a combination of lower efflux of PPIX and reduced synthesis and export of bile acid.
  
  
  CONCLUSIONS
  PPIX binds to bile components and disrupts the physiologic equilibrium of phospholipids, bile acids, and cholesterol in bile. This process might be involved in pathogenesis of sclerosing cholangitis from EPP; a better understanding might improve diagnosis and development of reagents to treat or prevent liver failure in patients with EPP.
authors.affiliation: INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris Diderot, site Bichat, Centre de reference des maladies inflammatoires des voies biliaires, service d’Hépatologie-Gastroentérologie, Hôpital Saint Antoine, Paris, France.
authors.forename: Saïd
authors.initials: S
authors.lastname: Lyoumi
authors.forename: Marie
authors.initials: M
authors.lastname: Abitbol
authors.forename: Dominique
authors.initials: D
authors.lastname: Rainteau
authors.forename: Zoubida
authors.initials: Z
authors.lastname: Karim
authors.forename: Florence
authors.initials: F
authors.lastname: Bernex
authors.forename: Vincent
authors.initials: V
authors.lastname: Oustric
authors.forename: Sarah
authors.initials: S
authors.lastname: Millot
authors.forename: Philippe
authors.initials: P
authors.lastname: Lettéron
authors.forename: Nicholas
authors.initials: N
authors.lastname: Heming
authors.forename: Laurent
authors.initials: L
authors.lastname: Guillmot
authors.forename: Xavier
authors.initials: X
authors.lastname: Montagutelli
authors.forename: Gilles
authors.initials: G
authors.lastname: Berdeaux
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005294:Ferrochelatase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D008073:Lipoprotein-X / Q000097:blood; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D017354:Point Mutation; D017092:Porphyria, Erythropoietic / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011524:Protoporphyrins / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D001647:Bile Acids and Salts; D008073:Lipoprotein-X; D010743:Phospholipids; D011524:Protoporphyrins; D002784:Cholesterol; C028025:protoporphyrin IX; D005294:Ferrochelatase