title: Changes of organic anion transporter MRP4 and related nuclear receptors in human obstructive cholestasis.
abstract: BACKGROUND
  Hepatic multidrug resistance-associated protein 4 (Mrp4) levels are low, but increase markedly in rodent cholestatic liver. Nuclear receptors (NRs) are essential for regulating Mrp4 expression in cholestasis models. However, information about MRP4 and related NRs, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoic X receptor-α (RXRα), is relatively lacking in human obstructive cholestasis. We collected liver samples from patients with obstructive cholestasis or without liver disease and investigated the expression of MRP4 and NRs CAR, PXR, and RXRα by semi-quantitative RT-PCR, Western blot and immunostaining assays.
  
  
  RESULTS
  MRP4 mRNA/protein levels were markedly increased in obstructive cholestasis. Concentration of serum total bile acids (TBA) was significantly correlated with MRP4 protein in cholestasis samples (P < 0.01). PXR and RXRα mRNA/protein levels were significantly increased in obstructive cholestasis. CAR mRNA levels were unchanged while protein levels were markedly induced in obstructive cholestasis. There was a statistically positive correlation between MRP4 mRNA and CAR protein (P < 0.05), suggesting that CAR may activate transcription of MRP4 genes by its nuclear translocation.
  
  
  CONCLUSIONS
  Hepatic MRP4 levels were dramatically induced in human obstructive cholestasis, which may reduce liver injury by increasing efflux of toxic bile acids from hepatocytes into blood.
authors.affiliation: Institute of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China. chaijinsw@yahoo.com
authors.forename: Jin
authors.initials: J
authors.lastname: Chai
authors.forename: Donglin
authors.initials: D
authors.lastname: Luo
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.forename: Huaizhi
authors.initials: H
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: He
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Peng
authors.forename: Tianli
authors.initials: T
authors.lastname: Xiao
authors.forename: Rongquan
authors.initials: R
authors.lastname: Wang
authors.forename: Wensheng
authors.initials: W
authors.lastname: Chen
mesh_terms: D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015153:Blotting, Western; D001651:Cholestasis, Extrahepatic / Q000378:metabolism*; D003135:Common Bile Duct / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001647:Bile Acids and Salts; D001663:Bilirubin; D000090702:Constitutive Androstane Receptor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; C073492:ABCC4 protein, human