Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes

U. Beuers, D. C. Throckmorton, M. S. Anderson, Carlos M Isales, W. Thasler, G. A. Kullak- Ublick, G. Sauter, H. G. Koebe, G. Paumgartner, J. L. Boyer

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Abstract

Background and Aims: Ursodeoxycholic acid (UDCA) improves liver function in patients with chronic cholestatic liver diseases by an unknown mechanism. UDCA is conjugated to taurine in vivo, and tauroursodeoxycholic acid (TUDCA) is a potent hepatocellular Ca2+ agonist and stimulates biliary exocytosis and hepatocellular Ca2+ influx, both of which are defective in experimental cholestasis. Protein kinase C (PKC) mediates stimulation of exocytosis in the liver. The aim of this study was to determine the effects of TUDCA on PKC in isolated hepatocytes. Methods: The effect of TUDCA on the distribution of PKC isoenzymes within the hepatocyte was studied using immunoblotting and immunofluorescence techniques. In addition, the effect of TUDCA on the accumulation of sn-1,2-diacylglycerol (DAG), the intracellular activator of PKC, and hepatocellular PKC activity was studied using radioenzymatic techniques. Results: Immunoblotting studies showed the presence of four isoenzymes (α, δ, ε, and ζ). The phorbol ester phorbol 12-myristate 13- acetate (1 μmol/L) induced translocation of α-PKC, δ-PKC, and ε-PKC from cytosol to a particulate membrane fraction, a key step for activation of PKC. TUDCA, but not taurocholic acid, selectively induced translocation of the α- PKC isoenzyme from cytosol to the membranes. In addition, TUDCA induced a significant increase in hepatocellular DAG mass and stimulated membrane- associated PKC activity. Conclusions: TUDCA might stimulate Ca2+-dependent hepatocellular exocytosis into bile in part by activation of α-PKC.

Original languageEnglish (US)
Pages (from-to)1553-1563
Number of pages11
JournalGastroenterology
Volume110
Issue number5
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Protein Kinase C
Hepatocytes
Exocytosis
Isoenzymes
Ursodeoxycholic Acid
Immunoblotting
Cytosol
tauroursodeoxycholic acid
Taurocholic Acid
Membranes
Liver
Taurine
Cholestasis
Phorbol Esters
Bile
Fluorescent Antibody Technique
Liver Diseases
Membrane Proteins
Acetates

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Beuers, U., Throckmorton, D. C., Anderson, M. S., Isales, C. M., Thasler, W., Kullak- Ublick, G. A., ... Boyer, J. L. (1996). Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology, 110(5), 1553-1563. https://doi.org/10.1053/gast.1996.v110.pm8613063

Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. / Beuers, U.; Throckmorton, D. C.; Anderson, M. S.; Isales, Carlos M; Thasler, W.; Kullak- Ublick, G. A.; Sauter, G.; Koebe, H. G.; Paumgartner, G.; Boyer, J. L.

In: Gastroenterology, Vol. 110, No. 5, 01.01.1996, p. 1553-1563.

Research output: Contribution to journalArticle

Beuers, U, Throckmorton, DC, Anderson, MS, Isales, CM, Thasler, W, Kullak- Ublick, GA, Sauter, G, Koebe, HG, Paumgartner, G & Boyer, JL 1996, 'Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes', Gastroenterology, vol. 110, no. 5, pp. 1553-1563. https://doi.org/10.1053/gast.1996.v110.pm8613063
Beuers U, Throckmorton DC, Anderson MS, Isales CM, Thasler W, Kullak- Ublick GA et al. Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. Gastroenterology. 1996 Jan 1;110(5):1553-1563. https://doi.org/10.1053/gast.1996.v110.pm8613063
Beuers, U. ; Throckmorton, D. C. ; Anderson, M. S. ; Isales, Carlos M ; Thasler, W. ; Kullak- Ublick, G. A. ; Sauter, G. ; Koebe, H. G. ; Paumgartner, G. ; Boyer, J. L. / Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes. In: Gastroenterology. 1996 ; Vol. 110, No. 5. pp. 1553-1563.
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abstract = "Background and Aims: Ursodeoxycholic acid (UDCA) improves liver function in patients with chronic cholestatic liver diseases by an unknown mechanism. UDCA is conjugated to taurine in vivo, and tauroursodeoxycholic acid (TUDCA) is a potent hepatocellular Ca2+ agonist and stimulates biliary exocytosis and hepatocellular Ca2+ influx, both of which are defective in experimental cholestasis. Protein kinase C (PKC) mediates stimulation of exocytosis in the liver. The aim of this study was to determine the effects of TUDCA on PKC in isolated hepatocytes. Methods: The effect of TUDCA on the distribution of PKC isoenzymes within the hepatocyte was studied using immunoblotting and immunofluorescence techniques. In addition, the effect of TUDCA on the accumulation of sn-1,2-diacylglycerol (DAG), the intracellular activator of PKC, and hepatocellular PKC activity was studied using radioenzymatic techniques. Results: Immunoblotting studies showed the presence of four isoenzymes (α, δ, ε, and ζ). The phorbol ester phorbol 12-myristate 13- acetate (1 μmol/L) induced translocation of α-PKC, δ-PKC, and ε-PKC from cytosol to a particulate membrane fraction, a key step for activation of PKC. TUDCA, but not taurocholic acid, selectively induced translocation of the α- PKC isoenzyme from cytosol to the membranes. In addition, TUDCA induced a significant increase in hepatocellular DAG mass and stimulated membrane- associated PKC activity. Conclusions: TUDCA might stimulate Ca2+-dependent hepatocellular exocytosis into bile in part by activation of α-PKC.",
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T1 - Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes

AU - Beuers, U.

AU - Throckmorton, D. C.

AU - Anderson, M. S.

AU - Isales, Carlos M

AU - Thasler, W.

AU - Kullak- Ublick, G. A.

AU - Sauter, G.

AU - Koebe, H. G.

AU - Paumgartner, G.

AU - Boyer, J. L.

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N2 - Background and Aims: Ursodeoxycholic acid (UDCA) improves liver function in patients with chronic cholestatic liver diseases by an unknown mechanism. UDCA is conjugated to taurine in vivo, and tauroursodeoxycholic acid (TUDCA) is a potent hepatocellular Ca2+ agonist and stimulates biliary exocytosis and hepatocellular Ca2+ influx, both of which are defective in experimental cholestasis. Protein kinase C (PKC) mediates stimulation of exocytosis in the liver. The aim of this study was to determine the effects of TUDCA on PKC in isolated hepatocytes. Methods: The effect of TUDCA on the distribution of PKC isoenzymes within the hepatocyte was studied using immunoblotting and immunofluorescence techniques. In addition, the effect of TUDCA on the accumulation of sn-1,2-diacylglycerol (DAG), the intracellular activator of PKC, and hepatocellular PKC activity was studied using radioenzymatic techniques. Results: Immunoblotting studies showed the presence of four isoenzymes (α, δ, ε, and ζ). The phorbol ester phorbol 12-myristate 13- acetate (1 μmol/L) induced translocation of α-PKC, δ-PKC, and ε-PKC from cytosol to a particulate membrane fraction, a key step for activation of PKC. TUDCA, but not taurocholic acid, selectively induced translocation of the α- PKC isoenzyme from cytosol to the membranes. In addition, TUDCA induced a significant increase in hepatocellular DAG mass and stimulated membrane- associated PKC activity. Conclusions: TUDCA might stimulate Ca2+-dependent hepatocellular exocytosis into bile in part by activation of α-PKC.

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