Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice

Am J Physiol Gastrointest Liver Physiol. 2002 Jan;282(1):G184-91. doi: 10.1152/ajpgi.00215.2001.

Abstract

Cholestasis is associated with retention of bile acids and reduced expression of the Na(+)/taurocholate cotransporter (Ntcp), the major hepatocellular bile acid uptake system. This study aimed to determine whether downregulation of Ntcp in obstructive cholestasis 1) is a consequence of bile acid retention and 2) is mediated by induction of the transcriptional repressor short heterodimer partner 1 (SHP-1). To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls. Serum bile acid levels were determined by radioimmunoassay. SHP-1 and Ntcp steady-state mRNA expression were assessed by Northern blotting. In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy. Increased SHP-1 mRNA expression paralleled elevations of serum bile acid levels and was followed by downregulation of Ntcp mRNA and protein expression in CBDL mice. Maximal SHP-1 mRNA expression reached a plateau phase after 6-h CBDL (12-fold; P < 0.001) and preceded the nadir of Ntcp mRNA levels (12%, P < 0.001) by 6 h. In conclusion, bile acid-induced expression of SHP-1 may, at least in part, mediate downregulation of Ntcp in CBDL mice. These findings support the concept that downregulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / blood
  • Bile Ducts / metabolism
  • Bile Ducts / physiopathology*
  • Blotting, Western
  • Carrier Proteins / analysis
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cholestasis, Extrahepatic / metabolism
  • Cholestasis, Extrahepatic / physiopathology*
  • Cholic Acid / pharmacology
  • Cytokines / physiology
  • Down-Regulation / physiology
  • Fluorescent Antibody Technique
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Ligation
  • Lipopolysaccharides / pharmacology
  • Male
  • Membrane Transport Proteins*
  • Mice
  • Mice, Inbred Strains
  • Organic Anion Transporters, Sodium-Dependent
  • RNA, Messenger / analysis
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Symporters

Substances

  • Bile Acids and Salts
  • Carrier Proteins
  • Cytokines
  • Lipopolysaccharides
  • Membrane Transport Proteins
  • Organic Anion Transporters, Sodium-Dependent
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Symporters
  • nuclear receptor subfamily 0, group B, member 2
  • sodium-bile acid cotransporter
  • Cholic Acid