title: Activation of LXRs prevents bile acid toxicity and cholestasis in female mice.
abstract: Liver X receptors (LXRs) have been identified as sterol sensors that regulate cholesterol and lipid homeostasis and macrophage functions. In this study, we found that LXRs also affect sensitivity to bile acid toxicity and cholestasis. Activation of LXRalpha in transgenic mice confers a female-specific resistance to lithocholic acid (LCA)-induced hepatotoxicity and bile duct ligation (BDL)-induced cholestasis. This resistance was also seen in wild-type female mice treated with the synthetic LXR ligand TO1317. In contrast, LXR double knockout (DKO) mice deficient in both the alpha and beta isoforms exhibited heightened cholestatic sensitivity. LCA and BDL resistance in transgenic mice was associated with increased expression of bile acid-detoxifying sulfotransferase 2A (Sult2a) and selected bile acid transporters, whereas basal expression of these gene products was reduced in the LXR DKO mice. Promoter analysis showed that the mouse Sult2a9 gene is a transcriptional target of LXRs. Activation of LXRs a l so suppresses expression of oxysterol 7alpha-hydroxylase (Cyp7b1), which may lead to increased levels of LXR-activating oxysterols.
  
  
  CONCLUSIONS
  We propose that LXRs have evolved to have the dual functions of maintaining cholesterol and bile acid homeostasis by increasing cholesterol catabolism and, at the same time, preventing toxicity from bile acid accumulation.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Hirdesh
authors.initials: H
authors.lastname: Uppal
authors.forename: Simrat P S
authors.initials: SP
authors.lastname: Saini
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
authors.forename: Ying
authors.initials: Y
authors.lastname: Mu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Haibiao
authors.initials: H
authors.lastname: Gong
authors.forename: Yonggong
authors.initials: Y
authors.lastname: Zhai
authors.forename: Songrong
authors.initials: S
authors.lastname: Ren
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000009:adverse effects* / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism / Q000517:prevention & control*; D002784:Cholesterol / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072474:Cytochrome P450 Family 7; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D006706:Homeostasis; D008095:Lithocholic Acid / Q000009:adverse effects / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D065607:Cytochrome P-450 Enzyme Inhibitors; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D008095:Lithocholic Acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse; D015238:Sulfotransferases; C019786:bile-salt sulfotransferase