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Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

Cited 48 time in Web of Science Cited 49 time in Scopus
Authors
Park, Young Joo; Qatanani, Mohammed; Chua, Steven S; LaRey, Jennifer L; Johnson, Stacy A; Watanabe, Mitsuhiro; Moore, David D; Lee, Yoon Kwang
Issue Date
2008-04-09
Publisher
Wiley-Blackwell
Citation
Hepatology, 2008;47(5):1578-86.
Keywords
AnimalsBile/secretionBile Ducts/*pathologyCholestasis/*pathologyCommon Bile Duct/pathologyCrosses, GeneticDNA-Binding Proteins/deficiencyDimerizationFemaleLiver/injuries/*pathologyMaleMiceMice, Inbred C57BLMice, KnockoutPolymerase Chain ReactionReceptors, Cell Surface/*deficiencyReceptors, Cytoplasmic and Nuclear/deficiencyTranscription Factors/deficiency
Abstract
The orphan nuclear hormone receptor small heterodimer partner (SHP) regulates the expression of several genes involved in bile acid homeostasis in the liver. Because bile acid toxicity is a major source of liver injury in cholestatic disease, we explored the role of SHP in liver damage induced by common bile duct ligation (BDL). Shp(-/-) mice show increased sensitivity in this model of acute obstructive cholestasis, with greater numbers of bile infarcts and higher mortality than wild-type C57BL/6 mice. This increased sensitivity could not be accounted for by differences in expression of bile acid homeostatic genes 2 or 5 days after BDL. Instead, higher basal expression of such genes, including the key biosynthetic enzyme cholesterol 7alpha hydroxylase (Cyp7A1) and the bile salt export pump, is associated with both an increase in bile flow prior to BDL and an increase in acute liver damage at only 1.5 hours after BDL in Shp(-/-) mice, as shown by bile infarcts. At 3 hours, Cyp7A1 expression still remained elevated in Shp(-/-) with respect to wild-type mice, and the hepatic and serum bile acid levels and total hepatobiliary bile acid pool were significantly increased. The increased sensitivity of mice lacking SHP contrasts with the decreased sensitivity of mice lacking the farnesoid X receptor (FXR; nuclear receptor subfamily 1, group H, member 4) to BDL, which has been associated with decreased intraductal pressure and fewer bile infarcts. Conclusion: We propose that differences in acute responses to BDL, particularly the early formation of bile infarcts, are a primary determinant of the differences in longer term sensitivity of the Fxr(-/-) and Shp(-/-) mice to acute obstructive cholestasis.
ISSN
1527-3350 (Electronic)
Language
English
URI
http://hdl.handle.net/10371/62208
DOI
https://doi.org/10.1002/hep.22196
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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