Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice.

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Research Abstract Details 

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Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Abstract Text:

Megan H Keane,Henk Overmars,Thomas M Wikander,Sacha Ferdinandusse,Marinus Duran,Ronald J A Wanders,Phyllis L Faust,

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. CONCLUSION: 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.

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Publishing Authors By Initials

MH Keane,H Overmars,TM Wikander,S Ferdinandusse,M Duran,RJ Wanders,PL Faust,

For similar digestive system diseases: liver diseases: zellweger syndrome research abstracts see: digestive system diseases: liver diseases: zellweger syndrome research

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Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Hepatology (Baltimore, Md.)

VOLUME: 45

Page Numbers: 982-97

Journal Abbreviation: Hepatology

ISSN: 0270-9139

DAY: 3

MONTH: Apr

YEAR: 2007

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Information

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LANGUAGE: eng

NlmUniqueID: 8302946

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Keywords Mesh Terms:

KEYWORDS: Zellweger Syndrome

MESH TERMS: pathology

Chemical & Substance for Abstract: Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Information

Substance Name: bile acid binding proteins

Registry Number: 0

Grant and Affiliation Information for Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice.

AFFILIATION: Department of Pathology, Columbia University, New York, NY 10032, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS050602

ACRONYM: NS

MEDLINETA: Hepatology

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