title: Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice.
abstract: The marked deficiency of peroxisomal organelle assembly in the PEX2(-/-) mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state. PEX2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36. We confirmed the expected reduction of mature C24 bile acids, accumulation of C27-bile acid intermediates, and low total bile acid level in liver and bile from these mutant mice. Treating the PEX2(-/-) mice with bile acids prolonged postnatal survival, alleviated intrahepatic cholestasis and intestinal malabsorption, reduced C27-bile acid intermediate production, and prevented older mutants from developing severe steatohepatitis. However, this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver. Both untreated and bile acid-fed PEX2(-/-) mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters. Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX2 mutants, indicating a generalized defect in bile acid conjugation.
  
  
  CONCLUSIONS
  Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice, and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease.
authors: Department of Pathology, Columbia University, New York, NY 10032, USA.
authors: Megan H
authors: MH
authors: Keane
authors: Henk
authors: H
authors: Overmars
authors: Thomas M
authors: TM
authors: Wikander
authors: Sacha
authors: S
authors: Ferdinandusse
authors: Marinus
authors: M
authors: Duran
authors: Ronald J A
authors: RJ
authors: Wanders
authors: Phyllis L
authors: PL
authors: Faust
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000473:pathology; D000074401:Peroxins; D015211:Zellweger Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000074401:Peroxins; C501732:Pex5l protein, mouse; C037643:bile acid binding proteins