title: Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents.
abstract: Organic solute transporter (OSTalpha-OSTbeta) is a novel heteromeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney, and liver. To determine whether OSTalpha-OSTbeta undergoes farnesoid X receptor (FXR)-dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild-type mice. Hepatic OSTalpha and OSTbeta mRNA increased 3- and 32-fold, respectively, in patients with PBC compared with controls, whereas expression of Ostalpha and Ostbeta also increased in the liver of rats and mice following CBDL. In contrast, expression of Ostalpha and Ostbeta mRNA was generally lower in Fxr null mice, and CBDL failed to enhance expression of Ostalpha and Ostbeta compared with wild-type mice. HepG2 cells treated for 24 h with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OSTalpha and OSTbeta mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ostalpha and Ostbeta are highly regulated in response to cholestasis and that this response is dependent on the FXR bile acid receptor.
authors.affiliation: Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA. james.boyer@yale.edu
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Albert
authors.initials: A
authors.lastname: Mennone
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Soroka
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Cai
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Ballatori
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002779:Cholestasis / Q000150:complications / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C476575:organic solute transporter alpha, human; C476577:SLC51B protein, human