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Tauroursodeoxycholic Acid (tauroursodeoxycholic + acid)
Selected AbstractsTauroursodeoxycholic acid mobilizes ,-PKC after uptake in human HepG2 hepatoma cellsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2002Helena Glasova Abstract Background Tauroursodeoxycholic acid (TUDCA) may exert anticholestatic effects via Ca++ - and ,-protein kinase C (,-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 ,-PKC, a key mediator of regulated exocytosis, to hepatocellular membranes. It is unclear whether TUDCA exerts its effects on ,-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 ,-PKC was studied using a Western blotting technique. Uptake of [3H]taurocholic acid (TCA) was determined radiochemically. Results [3H]taurocholic acid uptake was approximately 180-fold higher in Ntcp-transfected than in sham-transfected cells. Phorbol 12-myristate 13-acetate (1 µmol L,1; positive control) increased membrane binding of ,-PKC by 34% in Ntcp-transfected and by 37% in sham-transfected cells. Tauroursodeoxycholic acid (10 µmol L,1) increased membrane-associated ,-PKC by 19% in Ntcp-transfected, but not in sham-transfected cells (,13%). Taurocholic acid (10 µmol L,1) did not affect the distribution of ,-PKC. Conclusion Carrier-mediated uptake is a prerequisite for TUDCA-induced translocation of ,-PKC to hepatocellular membranes. [source] Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress,induced caspase-12 activationHEPATOLOGY, Issue 3 2002Qing Xie Activation of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of caspase-12 activation and its effect on calcium homeostasis in an ER stress-induced model of apoptosis. The human liver-derived cell line, Huh7, was treated with thapsigargin (TG) to induce ER stress. Typical morphologic changes of ER stress preceded development of apoptotic changes, including DNA fragmentation and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP), as well as activation of caspase-3 and -7. Elevation of intracellular calcium levels without loss of mitochondrial membrane potential (MMP) was shown using Fluo-3/Fura-red labeling and flow cytometry, and confirmed by induction of Bip/GRP78, a calcium-dependent chaperon of ER lumen. These changes were accompanied by procaspase-12 processing. TUDCA abolished TG-induced markers of ER stress; reduced calcium efflux, induction of Bip/GRP78, and caspase-12 activation; and subsequently inhibited activation of effector caspases and apoptosis. In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation. This novel mechanism of TUDCA action suggests new intervention methods for ER stress-induced liver disease. [source] | ||||||||||