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• W2040455679 abstract "Bile acids have been reported to induce epidermal growth factor receptor (EGFR) activation and subsequent proliferation of activated hepatic stellate cells (HSC), but the underlying mechanisms and whether quiescent HSC are also a target for bile acid-induced proliferation or apoptosis remained unclear. Therefore, primary rat HSC were cultured for up to 48 h and analyzed for their proliferative/apoptotic responses toward bile acids. Hydrophobic bile acids, i.e. taurolithocholate 3-sulfate, taurochenodeoxycholate, and glycochenodeoxycholate, but not taurocholate or tauroursodeoxycholate, induced Yes-dependent EGFR phosphorylation. Simultaneously, hydrophobic bile acids induced phosphorylation of the NADPH oxidase subunit p47phox and formation of reactive oxygen species (ROS). ROS production was sensitive to inhibition of acidic sphingomyelinase, protein kinase Cζ, and NADPH oxidases. All maneuvers which prevented bile acid-induced ROS formation also prevented Yes and subsequent EGFR phosphorylation. Taurolithocholate 3-sulfate-induced EGFR activation was followed by extracellular signal-regulated kinase 1/2, but not c-Jun N-terminal kinase (JNK) activation, and stimulated HSC proliferation. When, however, a JNK signal was induced by coadministration of cycloheximide or hydrogen peroxide (H2O2), activated EGFR associated with CD95 and triggered EGFR-mediated CD95-tyrosine phosphorylation and subsequent formation of the death-inducing signaling complex. In conclusion, hydrophobic bile acids lead to a NADPH oxidase-driven ROS generation followed by a Yes-mediated EGFR activation in quiescent primary rat HSC. This proliferative signal shifts to an apoptotic signal when a JNK signal simultaneously comes into play. Bile acids have been reported to induce epidermal growth factor receptor (EGFR) activation and subsequent proliferation of activated hepatic stellate cells (HSC), but the underlying mechanisms and whether quiescent HSC are also a target for bile acid-induced proliferation or apoptosis remained unclear. Therefore, primary rat HSC were cultured for up to 48 h and analyzed for their proliferative/apoptotic responses toward bile acids. Hydrophobic bile acids, i.e. taurolithocholate 3-sulfate, taurochenodeoxycholate, and glycochenodeoxycholate, but not taurocholate or tauroursodeoxycholate, induced Yes-dependent EGFR phosphorylation. Simultaneously, hydrophobic bile acids induced phosphorylation of the NADPH oxidase subunit p47phox and formation of reactive oxygen species (ROS). ROS production was sensitive to inhibition of acidic sphingomyelinase, protein kinase Cζ, and NADPH oxidases. All maneuvers which prevented bile acid-induced ROS formation also prevented Yes and subsequent EGFR phosphorylation. Taurolithocholate 3-sulfate-induced EGFR activation was followed by extracellular signal-regulated kinase 1/2, but not c-Jun N-terminal kinase (JNK) activation, and stimulated HSC proliferation. When, however, a JNK signal was induced by coadministration of cycloheximide or hydrogen peroxide (H2O2), activated EGFR associated with CD95 and triggered EGFR-mediated CD95-tyrosine phosphorylation and subsequent formation of the death-inducing signaling complex. In conclusion, hydrophobic bile acids lead to a NADPH oxidase-driven ROS generation followed by a Yes-mediated EGFR activation in quiescent primary rat HSC. This proliferative signal shifts to an apoptotic signal when a JNK signal simultaneously comes into play. Hydrophobic bile acids play a major role in the pathogenesis of cholestatic liver disease and are potent inducers of hepatocyte apoptosis by triggering a ligand-independent activation of the CD95 2The abbreviations used are: CD95Fas, APO-1, CD95 receptorBrdUrdbromodeoxyuridineCD95LCD95 ligandCHXcycloheximideCM-H2DCFDA5-(and-6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetateEGFRepidermal growth factor (EGR) receptorErkextracellular signal-regulated kinaseFADDFas-associated death domainGadd45βgrowth arrest and DNA damage-inducible gene 45βGCDCglycochenodeoxycholateHSChepatic stellate cellsJNKc-Jun N-terminal kinasep38MAPKp38 mitogen-activated protein kinasePKCζ inhibitorcell-permeable myristoylated PKCζ pseudosubstrateROSreactive oxygen speciesSMAsmooth muscle actinTCtaurocholateTCDCtaurochenodeoxycholateTLCStaurolithocholate 3-sulfateTUDCtauroursodeoxycholateTUNELTdT-mediated X-dUTP nick end labelingDISCdeath-inducing signaling complex. 2The abbreviations used are: CD95Fas, APO-1, CD95 receptorBrdUrdbromodeoxyuridineCD95LCD95 ligandCHXcycloheximideCM-H2DCFDA5-(and-6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetateEGFRepidermal growth factor (EGR) receptorErkextracellular signal-regulated kinaseFADDFas-associated death domainGadd45βgrowth arrest and DNA damage-inducible gene 45βGCDCglycochenodeoxycholateHSChepatic stellate cellsJNKc-Jun N-terminal kinasep38MAPKp38 mitogen-activated protein kinasePKCζ inhibitorcell-permeable myristoylated PKCζ pseudosubstrateROSreactive oxygen speciesSMAsmooth muscle actinTCtaurocholateTCDCtaurochenodeoxycholateTLCStaurolithocholate 3-sulfateTUDCtauroursodeoxycholateTUNELTdT-mediated X-dUTP nick end labelingDISCdeath-inducing signaling complex. death receptor (1Chieco P. Romagnoli E. Aicardi G. Suozzi A. Forti G.C. Roda A. Histochem. J. 1997; 29: 875-883Crossref PubMed Scopus (31) Google Scholar, 2Faubion W.A. Guicciardi M.E. Miyoshi H. Bronk S.F. Roberts P.J. Svingen P.A. Kaufmann S.H. Gores G.J. J. Clin. Invest. 1999; 103: 137-145Crossref PubMed Scopus (463) Google Scholar, 3Miyoshi H. Rust C. Roberts P.J. Burgart L.J. Gores G.J. Gastroenterology. 1999; 117: 669-677Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 4Yerushalmi B. Dahl R. Devereaux M.W. Gumpricht E. Sokol R.J. Hepatology. 2001; 33: 616-626Crossref PubMed Scopus (275) Google Scholar, 5Graf D. Kurz A.K. Fischer R. Reinehr R. Häussinger D. Gastroenterology. 2002; 122: 1411-1427Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). The underlying molecular mechanisms are complex and involve a Yes-dependent, but ligand-independent activation of the epidermal growth factor receptor (EGFR), which catalyzes CD95-tyrosine phosphorylation as a prerequisite for CD95 oligomerization, formation of the death-inducing signaling complex (DISC), and apoptosis induction (6Reinehr R. Graf D. Häussinger D. Gastroenterology. 2003; 125: 839-853Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 7Reinehr R. Becker S. Wettstein M. Häussinger D. Gastroenterology. 2004; 127: 1540-1557Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Bile acids also activate EGFR in cholangiocytes (8Werneburg N.W. Yoon J.H. Higuchi H. Gores G.J. Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 285: G31-G36Crossref PubMed Scopus (21) Google Scholar) and activated hepatic stellate cells (HSC) (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), however, the mechanisms underlying bile acid-induced EGFR activation in HSC remained unclear (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Surprisingly, bile acid-induced EGFR activation in HSC does not trigger apoptosis but results in a stimulation of cell proliferation (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). The behavior of quiescent HSC toward CD95 ligand (CD95L) is also unusual. CD95L, which is a potent inducer of hepatocyte apoptosis (10Galle P.R. Hofmann W.J. Walczak H. Schaller H. Otto G. Stremmel W. Krammer P.H. Runkel L. J. Exp. Med. 1995; 182: 1223-1230Crossref PubMed Scopus (675) Google Scholar, 11Kondo T. Suda T. Fukuyama H. Adachi M. Nagata S. Nat. Med. 1997; 3: 409-413Crossref PubMed Scopus (459) Google Scholar, 12Reinehr R. Schliess F. Häussinger D. FASEB J. 2003; 17: 731-733Crossref PubMed Scopus (100) Google Scholar), triggers activation of the EGFR in quiescent HSC, stimulates HSC proliferation, and simultaneously inhibits CD95-dependent death signaling through CD95-tyrosine nitration (13Reinehr R. Sommerfeld A. Häussinger D. Gastroenterology. 2008; 134: 1494-1506Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Similar observations were made with other death receptor ligands, i.e. tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) (13Reinehr R. Sommerfeld A. Häussinger D. Gastroenterology. 2008; 134: 1494-1506Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). The mitogenic action of CD95L in quiescent, 1–2-day cultured HSC is because of a c-Src-dependent shedding of EGF and subsequent auto/paracrine activation of the EGFR (13Reinehr R. Sommerfeld A. Häussinger D. Gastroenterology. 2008; 134: 1494-1506Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). This unusual behavior of quiescent HSC toward death receptor ligands may relate to the recent findings that quiescent HSC might represent a stem/progenitor cell compartment in the liver with a capacity to differentiate not only into myofibroblasts but also toward hepatocyte- and endothelial-like cells (14Kordes C. Sawitza I. Müller-Marbach A. Ale-Agha N. Keitel V. Klonowski-Stumpe H. Häussinger D. Biochem. Biophys. Res. Commun. 2007; 352: 410-417Crossref PubMed Scopus (197) Google Scholar). Thus, stimulation of HSC proliferation and resistance toward apoptosis in the hostile cytokine milieu accompanying liver injury may help HSC to play their role in liver regeneration. During cholestatic liver injury quiescent HSC are exposed to increased concentrations of circulating bile acids, but it is not known whether this may lead to HSC proliferation (as shown for activated HSC) (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), HSC apoptosis (as shown for hepatocytes) (1Chieco P. Romagnoli E. Aicardi G. Suozzi A. Forti G.C. Roda A. Histochem. J. 1997; 29: 875-883Crossref PubMed Scopus (31) Google Scholar, 2Faubion W.A. Guicciardi M.E. Miyoshi H. Bronk S.F. Roberts P.J. Svingen P.A. Kaufmann S.H. Gores G.J. J. Clin. Invest. 1999; 103: 137-145Crossref PubMed Scopus (463) Google Scholar, 3Miyoshi H. Rust C. Roberts P.J. Burgart L.J. Gores G.J. Gastroenterology. 1999; 117: 669-677Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 4Yerushalmi B. Dahl R. Devereaux M.W. Gumpricht E. Sokol R.J. Hepatology. 2001; 33: 616-626Crossref PubMed Scopus (275) Google Scholar, 5Graf D. Kurz A.K. Fischer R. Reinehr R. Häussinger D. Gastroenterology. 2002; 122: 1411-1427Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 6Reinehr R. Graf D. Häussinger D. Gastroenterology. 2003; 125: 839-853Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 7Reinehr R. Becker S. Wettstein M. Häussinger D. Gastroenterology. 2004; 127: 1540-1557Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), or both of them. Therefore, the aim of the current study was (a) to identify the molecular mechanisms underlying bile acid-induced EGFR activation and (b) to elucidate whether bile acid-induced signaling can couple to both cell proliferation and cell death in quiescent HSC.The present study shows that cholestatic bile acids trigger a rapid NADPH oxidase activation in quiescent HSC, which leads to a Yes-mediated EGFR phosphorylation and HSC proliferation. In contrast to hepatocytes, hydrophobic bile acids do not induce a JNK signal in HSC. However, when JNK activation is induced by coadministration of either cycloheximide (CHX) or hydrogen peroxide (H2O2), the bile acid-induced mitogenic signal is shifted to an apoptotic one. Hydrophobic bile acids play a major role in the pathogenesis of cholestatic liver disease and are potent inducers of hepatocyte apoptosis by triggering a ligand-independent activation of the CD95 2The abbreviations used are: CD95Fas, APO-1, CD95 receptorBrdUrdbromodeoxyuridineCD95LCD95 ligandCHXcycloheximideCM-H2DCFDA5-(and-6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetateEGFRepidermal growth factor (EGR) receptorErkextracellular signal-regulated kinaseFADDFas-associated death domainGadd45βgrowth arrest and DNA damage-inducible gene 45βGCDCglycochenodeoxycholateHSChepatic stellate cellsJNKc-Jun N-terminal kinasep38MAPKp38 mitogen-activated protein kinasePKCζ inhibitorcell-permeable myristoylated PKCζ pseudosubstrateROSreactive oxygen speciesSMAsmooth muscle actinTCtaurocholateTCDCtaurochenodeoxycholateTLCStaurolithocholate 3-sulfateTUDCtauroursodeoxycholateTUNELTdT-mediated X-dUTP nick end labelingDISCdeath-inducing signaling complex. 2The abbreviations used are: CD95Fas, APO-1, CD95 receptorBrdUrdbromodeoxyuridineCD95LCD95 ligandCHXcycloheximideCM-H2DCFDA5-(and-6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetateEGFRepidermal growth factor (EGR) receptorErkextracellular signal-regulated kinaseFADDFas-associated death domainGadd45βgrowth arrest and DNA damage-inducible gene 45βGCDCglycochenodeoxycholateHSChepatic stellate cellsJNKc-Jun N-terminal kinasep38MAPKp38 mitogen-activated protein kinasePKCζ inhibitorcell-permeable myristoylated PKCζ pseudosubstrateROSreactive oxygen speciesSMAsmooth muscle actinTCtaurocholateTCDCtaurochenodeoxycholateTLCStaurolithocholate 3-sulfateTUDCtauroursodeoxycholateTUNELTdT-mediated X-dUTP nick end labelingDISCdeath-inducing signaling complex. death receptor (1Chieco P. Romagnoli E. Aicardi G. Suozzi A. Forti G.C. Roda A. Histochem. J. 1997; 29: 875-883Crossref PubMed Scopus (31) Google Scholar, 2Faubion W.A. Guicciardi M.E. Miyoshi H. Bronk S.F. Roberts P.J. Svingen P.A. Kaufmann S.H. Gores G.J. J. Clin. Invest. 1999; 103: 137-145Crossref PubMed Scopus (463) Google Scholar, 3Miyoshi H. Rust C. Roberts P.J. Burgart L.J. Gores G.J. Gastroenterology. 1999; 117: 669-677Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 4Yerushalmi B. Dahl R. Devereaux M.W. Gumpricht E. Sokol R.J. Hepatology. 2001; 33: 616-626Crossref PubMed Scopus (275) Google Scholar, 5Graf D. Kurz A.K. Fischer R. Reinehr R. Häussinger D. Gastroenterology. 2002; 122: 1411-1427Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). The underlying molecular mechanisms are complex and involve a Yes-dependent, but ligand-independent activation of the epidermal growth factor receptor (EGFR), which catalyzes CD95-tyrosine phosphorylation as a prerequisite for CD95 oligomerization, formation of the death-inducing signaling complex (DISC), and apoptosis induction (6Reinehr R. Graf D. Häussinger D. Gastroenterology. 2003; 125: 839-853Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 7Reinehr R. Becker S. Wettstein M. Häussinger D. Gastroenterology. 2004; 127: 1540-1557Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Bile acids also activate EGFR in cholangiocytes (8Werneburg N.W. Yoon J.H. Higuchi H. Gores G.J. Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 285: G31-G36Crossref PubMed Scopus (21) Google Scholar) and activated hepatic stellate cells (HSC) (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), however, the mechanisms underlying bile acid-induced EGFR activation in HSC remained unclear (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Surprisingly, bile acid-induced EGFR activation in HSC does not trigger apoptosis but results in a stimulation of cell proliferation (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). The behavior of quiescent HSC toward CD95 ligand (CD95L) is also unusual. CD95L, which is a potent inducer of hepatocyte apoptosis (10Galle P.R. Hofmann W.J. Walczak H. Schaller H. Otto G. Stremmel W. Krammer P.H. Runkel L. J. Exp. Med. 1995; 182: 1223-1230Crossref PubMed Scopus (675) Google Scholar, 11Kondo T. Suda T. Fukuyama H. Adachi M. Nagata S. Nat. Med. 1997; 3: 409-413Crossref PubMed Scopus (459) Google Scholar, 12Reinehr R. Schliess F. Häussinger D. FASEB J. 2003; 17: 731-733Crossref PubMed Scopus (100) Google Scholar), triggers activation of the EGFR in quiescent HSC, stimulates HSC proliferation, and simultaneously inhibits CD95-dependent death signaling through CD95-tyrosine nitration (13Reinehr R. Sommerfeld A. Häussinger D. Gastroenterology. 2008; 134: 1494-1506Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Similar observations were made with other death receptor ligands, i.e. tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) (13Reinehr R. Sommerfeld A. Häussinger D. Gastroenterology. 2008; 134: 1494-1506Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). The mitogenic action of CD95L in quiescent, 1–2-day cultured HSC is because of a c-Src-dependent shedding of EGF and subsequent auto/paracrine activation of the EGFR (13Reinehr R. Sommerfeld A. Häussinger D. Gastroenterology. 2008; 134: 1494-1506Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). This unusual behavior of quiescent HSC toward death receptor ligands may relate to the recent findings that quiescent HSC might represent a stem/progenitor cell compartment in the liver with a capacity to differentiate not only into myofibroblasts but also toward hepatocyte- and endothelial-like cells (14Kordes C. Sawitza I. Müller-Marbach A. Ale-Agha N. Keitel V. Klonowski-Stumpe H. Häussinger D. Biochem. Biophys. Res. Commun. 2007; 352: 410-417Crossref PubMed Scopus (197) Google Scholar). Thus, stimulation of HSC proliferation and resistance toward apoptosis in the hostile cytokine milieu accompanying liver injury may help HSC to play their role in liver regeneration. During cholestatic liver injury quiescent HSC are exposed to increased concentrations of circulating bile acids, but it is not known whether this may lead to HSC proliferation (as shown for activated HSC) (9Svegliati-Baroni G. Ridolfi F. Hannivoort R. Saccomanno S. Homan M. De Minicis S. Jansen P.L. Candelaresi C. Benedetti A. Moshage H. Gastroenterology. 2005; 128: 1042-1055Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), HSC apoptosis (as shown for hepatocytes) (1Chieco P. Romagnoli E. Aicardi G. Suozzi A. Forti G.C. Roda A. Histochem. J. 1997; 29: 875-883Crossref PubMed Scopus (31) Google Scholar, 2Faubion W.A. Guicciardi M.E. Miyoshi H. Bronk S.F. Roberts P.J. Svingen P.A. Kaufmann S.H. Gores G.J. J. Clin. Invest. 1999; 103: 137-145Crossref PubMed Scopus (463) Google Scholar, 3Miyoshi H. Rust C. Roberts P.J. Burgart L.J. Gores G.J. Gastroenterology. 1999; 117: 669-677Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 4Yerushalmi B. Dahl R. Devereaux M.W. Gumpricht E. Sokol R.J. Hepatology. 2001; 33: 616-626Crossref PubMed Scopus (275) Google Scholar, 5Graf D. Kurz A.K. Fischer R. Reinehr R. Häussinger D. Gastroenterology. 2002; 122: 1411-1427Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 6Reinehr R. Graf D. Häussinger D. Gastroenterology. 2003; 125: 839-853Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 7Reinehr R. Becker S. Wettstein M. Häussinger D. Gastroenterology. 2004; 127: 1540-1557Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), or both of them. Therefore, the aim of the current study was (a) to identify the molecular mechanisms underlying bile acid-induced EGFR activation and (b) to elucidate whether bile acid-induced signaling can couple to both cell proliferation and cell death in quiescent HSC. Fas, APO-1, CD95 receptor bromodeoxyuridine CD95 ligand cycloheximide 5-(and-6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate epidermal growth factor (EGR) receptor extracellular signal-regulated kinase Fas-associated death domain growth arrest and DNA damage-inducible gene 45β glycochenodeoxycholate hepatic stellate cells c-Jun N-terminal kinase p38 mitogen-activated protein kinase cell-permeable myristoylated PKCζ pseudosubstrate reactive oxygen species smooth muscle actin taurocholate taurochenodeoxycholate taurolithocholate 3-sulfate tauroursodeoxycholate TdT-mediated X-dUTP nick end labeling death-inducing signaling complex. Fas, APO-1, CD95 receptor bromodeoxyuridine CD95 ligand cycloheximide 5-(and-6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate epidermal growth factor (EGR) receptor extracellular signal-regulated kinase Fas-associated death domain growth arrest and DNA damage-inducible gene 45β glycochenodeoxycholate hepatic stellate cells c-Jun N-terminal kinase p38 mitogen-activated protein kinase cell-permeable myristoylated PKCζ pseudosubstrate reactive oxygen species smooth muscle actin taurocholate taurochenodeoxycholate taurolithocholate 3-sulfate tauroursodeoxycholate TdT-mediated X-dUTP nick end labeling death-inducing signaling complex. The present study shows that cholestatic bile acids trigger a rapid NADPH oxidase activation in quiescent HSC, which leads to a Yes-mediated EGFR phosphorylation and HSC proliferation. In contrast to hepatocytes, hydrophobic bile acids do not induce a JNK signal in HSC. However, when JNK activation is induced by coadministration of either cycloheximide (CHX) or hydrogen peroxide (H2O2), the bile acid-induced mitogenic signal is shifted to an apoptotic one. Supplementary Material Download .pdf (.4 MB) Help with pdf files Download .pdf (.4 MB) Help with pdf files" @default.
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• W2040455679 title "Bile Acid-induced Epidermal Growth Factor Receptor Activation in Quiescent Rat Hepatic Stellate Cells Can Trigger Both Proliferation and Apoptosis" @default.
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