Prevention of cholesterol gallstone disease by FXR agonists in a mouse model.
Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we describe the same phenotype in mice lacking the bile acid receptor, FXR. Furthermore, in susceptible wild-type mice that recapitulate human cholesterol gallstone disease, treatment with a synthetic FXR agonist prevented sequelae of the disease. These effects were mediated by FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation. Taken together, these results indicate that FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease.
Moschetta
Antonio
A
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9050, USA.
Bookout
Angie L
AL
Mangelsdorf
David J
DJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000819:agonists*; D005704:Gallbladder / Q000473:pathology; D042882:Gallstones / Q000188:drug therapy / Q000517:prevention & control*; D015870:Gene Expression; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000819:agonists*; D000099150:Receptor, Farnesoid X-Activated
D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002784:Cholesterol; D017931:DNA Primers; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D010743:Phospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064