Retrieval of the rat canalicular conjugate export pump Mrp2 is associated with a rearrangement of actin filaments and radixin in bile salt-induced cholestasis

Eur J Med Res. 2008 Jul 28;13(7):314-8.

Abstract

Bile salts may initiate or aggravate cholestasis in man. Infusion of Taurochenodeoxycholate (TCDCA) represents a model of bile salt-induced cholestasis in rat. The events leading to cholestasis are incompletely understood. The canalicular conjugate export pump Mrp2 is the major driving force for the bile salt-independent bile flow. Redistribution of Mrp2 has been suggested to cause reduction in bile flow in others models of acute cholestasis (i.e. endotoxin, phalloidin, GSH-depletion). We have studied the effects of TCDCA on the distribution of Mrp2 and P-glycoproteins with respect to changes in the actin cytoskeleton and actin associated proteins radixin and ZO-1. Bile duct cannulated rats were infused with TCDCA (0.1 and 0.4 micromol/min/100g body weight) and bile flow was measured. After 30 min livers were removed and distribution of Mrp2, P-glycoproteins, actin, actin-associated radixin and ZO1 were studied by immunofluorescence analysis. TCDCA at subcholestatic amounts (0.1 micromol/min/100 g body weight) led to distortion and dilation of the canaliculi which was apparent in actin, ZO-1, and Mrp2 fluorescence. Administration of higher amounts of TCDCA (0.4 micromol/min/100g body weight) led to a reduction of bile flow to 31 % of control bile flow. Radixin, which localized strictly to the plasmamembrane in controls, was detected in intracellular structures partially colocalizing with actin aggregates especially at the sinusoidal membranes as visualized by double-immunofluorescence staining. Mrp2 appeared in pericanalicular membrane structures in cholestatic animals whereas P-glycoproteins remained unchanged under these conditions.

Conclusions: Bile salt-induced cholestasis is associated with changes of the actin cytoskeleton and actin binding protein radixin and a retrieval of the canalicular export pump Mrp2.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / metabolism*
  • Actin Cytoskeleton / chemistry*
  • Actin Cytoskeleton / metabolism
  • Animals
  • Bile Acids and Salts / chemistry*
  • Bile Ducts / pathology
  • Cholestasis / chemically induced*
  • Cytoskeletal Proteins / chemistry*
  • Humans
  • Male
  • Membrane Proteins / chemistry*
  • Microscopy, Fluorescence / methods
  • Models, Biological
  • Rats
  • Rats, Wistar
  • Time Factors

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Bile Acids and Salts
  • Cytoskeletal Proteins
  • Membrane Proteins
  • radixin