Document Detail


PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts.
MedLine Citation:
PMID:  21354151     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Cholesterol gallstone disease (CGD) results from a biochemical imbalance of lipids and bile salts in the gallbladder bile. We investigated whether the xenobiotic receptor pregnane X receptor (PXR) has a role in pathogenesis of CGD.
METHODS: Wild-type, PXR-null (PXR-/-), and CGD-sensitive C57L mice were placed on a lithogenic diet and then analyzed for CGD at the biochemical, histological, and gene-regulation levels.
RESULTS: Loss of PXR sensitized mice to lithogenic diet-induced CGD, characterized by decreases in biliary concentrations of bile salts and phospholipids and an increases in the cholesterol saturation index and formation of cholesterol crystals. The decreased bile acid pool size in PXR-/- mice that received lithogenic diets was associated with reduced expression of cholesterol 7α-hydroxylase, the rate-limiting enzyme of cholesterol catabolism and bile acid formation. The reduced expression of cholesterol 7α-hydroxylase most likely resulted from activation of farnesoid X receptor and induction of fibroblast growth factor 15 in the intestine. In C57L mice given the PXR agonist, pregnenolone-16α-carbonitrile, or the herbal medicine, St John's wort, cholesterol precipitation was prevented by increases in concentrations of biliary bile salt and a reduced cholesterol saturation index. PXR prevented CGD via its coordinate regulation of the biosynthesis and transport of bile salts in the liver and intestine.
CONCLUSIONS: PXR maintains biliary bile acid homeostasis and may be developed as a therapeutic target for CGD.
Authors:
Jinhan He; Shigeru Nishida; Meishu Xu; Makoto Makishima; Wen Xie
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-02-24
Journal Detail:
Title:  Gastroenterology     Volume:  140     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-06     Completed Date:  2011-08-09     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2095-106     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bile / metabolism*
Bile Acids and Salts / metabolism*
Biological Transport
Cholesterol 7-alpha-Hydroxylase / metabolism
Cholesterol, Dietary / metabolism*
Disease Models, Animal
Fibroblast Growth Factors / metabolism
Gallstones / genetics,  metabolism,  prevention & control*
Gene Expression Regulation
Hypericum
Intestines / drug effects,  metabolism*
Liver / drug effects,  metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phospholipids / metabolism
Plant Preparations / pharmacology
Pregnenolone Carbonitrile / pharmacology
Receptors, Cytoplasmic and Nuclear / metabolism
Receptors, Steroid / agonists,  deficiency,  genetics,  metabolism*
Time Factors
Grant Support
ID/Acronym/Agency:
DK083952/DK/NIDDK NIH HHS; ES014626/ES/NIEHS NIH HHS; R01 DK076962/DK/NIDDK NIH HHS; R01 DK076962-02/DK/NIDDK NIH HHS; R01 DK083952/DK/NIDDK NIH HHS; R01 DK083952-01A1/DK/NIDDK NIH HHS; R01 DK083952-02/DK/NIDDK NIH HHS; R01 ES014626/ES/NIEHS NIH HHS; R01 ES014626-05/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Cholesterol, Dietary; 0/Phospholipids; 0/Plant Preparations; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Steroid; 0/farnesoid X-activated receptor; 0/fibroblast growth factor 15, mouse; 0/pregnane X receptor; 1434-54-4/Pregnenolone Carbonitrile; 62031-54-3/Fibroblast Growth Factors; EC 1.14.13.17/Cholesterol 7-alpha-Hydroxylase
Comments/Corrections

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