Phosphatidylinositol 3-kinase-dependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers

Rust, Christian; Bauchmüller, Kris; Fickert, Peter; Fuchsbichler, Andrea; Beuers, Ulrich

doi:10.1152/ajpgi.00450.2004

Cited by 33 publications

(30 citation statements)

References 35 publications

(40 reference statements)

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“…Bile acid taurochenodeoxycholic acid activates the AKT pathway in mouse primary hepatocytes 25 and in perfused rat liver. 26 The constitutively active form of AKT protected primary cultured rat hepatocytes from apoptosis induced by Ad5I B plus TNF-␣ (data not shown) as previously reported, 8,23 and phosphatidylinositol 3-kinase inhibitor LY294002 has a proapoptotic effect on primary cultured hepatocytes. 15 BDL also induces a de novo expression of Bcl-2 in hepatocytes 27 (data not shown).…”

Section: Discussionsupporting

confidence: 74%

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

et al. 2005

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Section: Discussionsupporting

confidence: 74%

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

et al. 2005

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“…TCDC has been described to coactivate phosphatidylinositol 3-kinase (PI3K)-dependent survival pathways in hepatocytes. 38 This molecular mechanism could be an alternative explanation for reduced toxicity of TCDC, in comparison to CDC and GCDC, in cholangiocytes. Therefore, the experiments described above were repeated in the presence or absence of wortmannin, a potent PI3K inhibitor.…”

Section: Resultsmentioning

confidence: 99%

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

et al. 2011

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Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized that an apical biliary HCO À 3 umbrella might prevent the protonation of biliary glycine-conjugated bile salts and uncontrolled cell entry of the corresponding bile acids, and that defects in this biliary HCO À 3 umbrella might predispose to chronic cholangiopathies. Here, we tested in vitro whether human cholangiocyte integrity in the presence of millimolar bile salt monomers is dependent on (1) pH, (2) adequate expression of the key HCO À 3 exporter, anion exchanger 2 (AE2), and (3) an intact cholangiocyte glycocalyx. To address these questions, human immortalized cholangiocytes and cholangiocarcinoma cells were exposed to chenodeoxycholate and its glycine/taurine conjugates at different pH levels. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral short hairpin RNA. A cholangiocyte glycocalyx was identified by electron microscopy, was enzymatically desialylated, and sialylation was quantified by flow cytometry. We found that bile acid uptake and toxicity in human immortalized cholangiocytes and cholangiocarcinoma cell lines in vitro were pH and AE2 dependent, with the highest rates at low pH and when AE2 expression was defective. An apical glycocalyx was identified on cholangiocytes in vitro by electron microscopic techniques. Desialylation of this protective layer increased cholangiocellular vulnerability in a pH-dependent manner. Conclusion: A biliary HCO À 3 umbrella protects human cholangiocytes against damage by bile acid monomers. An intact glycocalyx and adequate AE2 expression are crucial in this process. Defects of the biliary HCO À 3 umbrella may lead to the development of chronic cholangiopathies.

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“…The exact mechanisms of bile acid-induced pancreatitis in experimental models (1,17) are not well established and are thought to be through their "blunt" effect as detergents. However, data acquired in different cell types, including the pancreatic acinar cell, have indicated that bile acids regulate specific cellular signals, in particular, [Ca 2ϩ ] i responses (8,13,14,25,31,34). These data also demonstrated a possible role of PI3K in bile acid-induced signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca²⁺responses in pancreatic acinar cells

Fischer

Gukovskaya²,

Penninger³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Phosphatidylinositol 3-kinase-dependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers

Abstract: Rust, Christian, Kris Bauchmuller, Peter Fickert, Andrea Fuchsbichler, and Ulrich Beuers. Phosphatidylinositol 3-kinasedependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers.

Cited by 33 publications

References 35 publications

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca²⁺responses in pancreatic acinar cells

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Phosphatidylinositol 3-kinase-dependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers

Abstract: Rust, Christian, Kris Bauchmuller, Peter Fickert, Andrea Fuchsbichler, and Ulrich Beuers. Phosphatidylinositol 3-kinasedependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers.

Cited by 33 publications

References 35 publications

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

A biliary HCO3−umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca2+responses in pancreatic acinar cells

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A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca²⁺responses in pancreatic acinar cells