Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Liang QiaoPaul Dent

Abstract

The mechanisms by which bile acids induce apoptosis in hepatocytes and the signaling pathways involved in the control of cell death are not understood fully. Here, we examined the impact of mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K) signaling on the survival of primary hepatocytes exposed to bile acids. Treatment of hepatocytes with deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) caused sustained MAPK activation that was dependent on activation of the epidermal growth factor receptor (EGFR). Activation of MAPK was partially blocked by inhibitors of PI3K. Inhibition of DCA-, CDCA-, and UDCA-stimulated MAPK activation resulted in approximately 20%, approximately 35%, and approximately 55% apoptosis, respectively. The potentiation of DCA- and CDCA-induced apoptosis by MEK1/2 inhibitors correlated with cleavage of procaspase 3, which was blocked by inhibitors of caspase 8 (ile-Glu-Thr-Asp-p-nitroanilide [IETD]) and caspase 3 (DEVD). In contrast, the potentiation of UDCA-induced apoptosis weakly correlated with procaspase 3 cleavage, yet this effect was also blocked by IETD and DEVD. Incubation of hepatocytes with the serine protease inhibitor AEBSF reduced t...Continue Reading

References

Nov 1, 1990·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·D L SchmuckerK Kitani
Dec 1, 1994·The Journal of Clinical Investigation·T PatelG J Gores
Oct 6, 1997·Lancet·J Neuberger
Oct 27, 1997·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·R D Duan, A Nilsson
Apr 29, 1998·Artificial Organs·H NotoS Todo
Jun 2, 1998·Seminars in Liver Disease·A Celli, F G Que
Jan 12, 1999·The Journal of Clinical Investigation·W A FaubionG J Gores
Jul 27, 1999·European Journal of Gastroenterology & Hepatology·E J Heathcote
Jul 29, 1999·Journal of Hepatology·M TraunerJ L Boyer
Aug 28, 1999·Gastroenterology·H MiyoshiG J Gores
Oct 16, 1999·Scandinavian Journal of Gastroenterology·Y ChengR D Duan
Feb 11, 2000·Radiation Research·R K Schmidt-UllrichK Valerie
Mar 18, 2000·The Journal of Biological Chemistry·T LinD R Green
Mar 23, 2000·Journal of Hepatology·R PouponR E Poupon
Mar 29, 2000·Gastroenterology·P W Marcello
Jun 2, 2000·The Journal of Membrane Biology·W StruppC Jassoy
Jun 22, 2000·American Journal of Physiology. Gastrointestinal and Liver Physiology·T SodemanG J Gores
Sep 23, 2000·Chemistry and Physics of Lipids·S Chatterjee
Feb 13, 2001·Biochemical and Biophysical Research Communications·A D TepperW J van Blitterswijk
Apr 5, 2001·The Journal of Biological Chemistry·A CremestiR Kolesnick

❮ Previous
Next ❯

Citations

Apr 6, 2004·Clinics in Liver Disease·Gustav Paumgartner, Ulrich Beuers
Jul 23, 2002·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·M E Guicciardi, G J Gores
Aug 29, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Gustav Paumgartner, Ulrich Beuers
Jan 9, 2010·Antioxidants & Redox Signaling·Kazuhito KawataHirotoshi Nakamura
Aug 15, 2008·Molecular Plant-microbe Interactions : MPMI·Caixia LiWallace A Cowling
Feb 11, 2005·Current Opinion in Gastroenterology·Michael Trauner, James L Boyer
Nov 1, 2006·Journal of Gastroenterology and Hepatology·Fuminori HiranoIsao Makino
Nov 14, 2007·Gut·Raoul Poupon, Lawrence Serfaty
Apr 7, 2009·Journal of Lipid Research·Phillip B HylemonPaul Dent
May 7, 2009·Journal of Lipid Research·Joana D AmaralCecília M P Rodrigues
Apr 2, 2005·Biological & Pharmaceutical Bulletin·Kaori HiramatsuEiichi Gohda
Aug 21, 2013·PloS One·Titia E Woudenberg-VrenkenHan Moshage
Apr 11, 2009·World Journal of Gastroenterology : WJG·Maria-J Perez, Oscar Briz
May 2, 2003·Proceedings of the National Academy of Sciences of the United States of America·Cecilia M P RodriguesClifford J Steer
May 30, 2014·Apoptosis : an International Journal on Programmed Cell Death·Karen BannertBrigitte Vollmar
Mar 27, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·M Eugenia Guicciardi, Gregory J Gores
Jun 28, 2014·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·UNKNOWN ALSUntangled Group
Nov 13, 2012·Clinics and Research in Hepatology and Gastroenterology·Fabia Liechti, Jean-François Dufour
Mar 5, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Gaetano ServiddioJuan Sastre
Jul 24, 2012·Biochemical Pharmacology·Yuki IkebuchiHiroshi Suzuki
Sep 7, 2007·Journal of Neuropathology and Experimental Neurology·Adelaide FernandesDora Brites
Oct 25, 2008·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·M MarzioniA Benedetti
Feb 5, 2008·Clinics in Liver Disease·George E N Kass, Shirley C Price
Apr 30, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Lifu WangJean-François Dufour
Apr 9, 2005·Alimentary Pharmacology & Therapeutics·S N Cullen, R W Chapman
Jun 6, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Walee ChamulitratWolfgang Stremmel
Apr 2, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jacquelyn J Maher
May 30, 2003·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Mark J CzajaYongjun Wang
Feb 10, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Song Iy HanPaul Dent

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