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Tauroursodeoxycholic acid mobilizes alpha-PKC after uptake in human HepG2 hepatoma cells
Helena Glasova1, Thomas M Berghaus, Gerd A Kullak-Ublick
1Department of Medicine II, Klinikum Grosshadern, University of Munich, Germany.
Background:
Tauroursodeoxycholic acid (TUDCA) may exert anticholestatic effects via Ca(++)- and alpha-protein kinase C (alpha-PKC)-dependent apical vesicular insertion of canalicular transporters in cholestatic hepatocytes (Hepatology 2001; 33: 1206-16). Tauroursodeoxycholic acid is mainly taken up into liver cells by Na(+)-taurocholate cotransporting polypeptide (Ntcp). Tauroursodeoxycholic acid selectively translocates alpha-PKC, a key mediator of regulated exocytosis, to hepatocellular membranes. It is unclear whether TUDCA exerts its effects on alpha-PKC after carrier-mediated uptake into liver cells or by interaction with extracellular/membraneous structures.
Materials And Methods:
Human hepatoblastoma HepG2 cells lacking Ntcp were stably transfected with pcDNA3.1/Ntcp or sham-transfected with pcDNA3.1 [+]. Distribution of alpha-PKC was studied using a Western blotting technique. Uptake of [(3)H]taurocholic acid (TCA) was determined radiochemically.
Results:
[(3)H]taurocholic acid uptake was approximately 180-fold higher in Ntcp-transfected than in sham-transfected cells. Phorbol 12-myristate 13-acetate (1 micromol L(-1); positive control) increased membrane binding of alpha-PKC by 34% in Ntcp-transfected and by 37% in sham-transfected cells. Tauroursodeoxycholic acid (10 micromol L(-1)) increased membrane-associated alpha-PKC by 19% in Ntcp-transfected, but not in sham-transfected cells (-13%). Taurocholic acid (10 micromol L(-1)) did not affect the distribution of alpha-PKC.
Conclusion:
Carrier-mediated uptake is a prerequisite for TUDCA-induced translocation of alpha-PKC to hepatocellular membranes.
