title: PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts.
abstract: OBJECTIVE
  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.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15621, USA.
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nishida
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000378:metabolism*; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000378:metabolism; D042882:Gallstones / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005786:Gene Expression Regulation; D020902:Hypericum; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010743:Phospholipids / Q000378:metabolism; D028321:Plant Preparations / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D005346:Fibroblast Growth Factors; D010743:Phospholipids; D028321:Plant Preparations; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse