Regulation of the dynamic localization of the rat Bsep gene-encoded bile salt export pump by anisoosmolarity

Schmitt, Marcus

doi:10.1053/jhep.2001.22648

Cited by 83 publications

(81 citation statements)

References 67 publications

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“…44 In contrast, NADPH-dependent ROS formation (oxidative stress) triggers cell shrinkage and cholestasis by endocytosis of Bsep/Mrp2. 5,31,53 In this study we show that TCDC induce PKC-and PP2B-mediated inhibition of sinusoidal TC uptake, most likely by internalization of Ntcp. This is counteracted by the PI3K.…”

Section: Tcdc Induces Redistribution Of Ntcp In Perfusedmentioning

confidence: 49%

“…Maintenance of bile salt homeostasis is important because bile salts exert many biological effects in liver and extrahepatic organs. 27 Long-term adaptation of bile salt transporters involves changes at the messenger RNA (mRNA) and protein levels, 28 whereas covalent modifications (e.g., phosphorylation), 29 substrate availability, 30 or rapid endo-and exocytosis of transporter-containing vesicles 19,31 represent modalities of short-term regulation. Current concepts assume mechanisms that would limit intracellular accumulation of potentially toxic bile salts under cholestatic conditions.…”

Section: Discussionmentioning

confidence: 99%

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Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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The sodium taurocholate cotransporting polypeptide (Ntcp) is the major bile salt uptake transporter at the sinusoidal membrane of hepatocytes. Short-term feedback regulation of Ntcp by primary bile salts has not yet been investigated in vivo. Subcellular localization of Ntcp was analyzed in Ntcp-transfected HepG2-cells by flow cytometry and in immunofluorescence images from tissue sections by a new automated image analysis method. Net bile salt uptake was investigated in perfused rat liver by a pulse chase technique. In Flag-Ntcp-EGFP (enhanced green fluorescent protein) expressing HepG2-cells, taurochenodeoxycholate (TCDC), but not taurocholate (TC), induced endocytosis of Ntcp. TCDC, but not TC, caused significant internalization of Ntcp in perfused rat livers, as shown by an increase in intracellular Ntcp immunoreactivity, whereas Bsep distribution remained unchanged. These results correlate with functional studies. Rat livers were continuously perfused with 100 mu mol/L of TC. 25 mu mol/L of TCDC, taurodeoxycholate (TDC), tauroursodeoxycholate (TUDC), or TC were added for 30 minutes, washed out, followed by a pulse of (3)[H]-TC. TCDC, but not TDC, TUDC, or TC significantly increased the amount of (3)[H]-TC in the effluent, indicating a reduced sinusoidal net TC uptake. This effect was sensitive to chelerythrine (protein kinase C inhibitor) and cypermethrin (protein phosphatase 2B inhibitor). Phosphoinositide 3-kinase (PI3K) inhibitors had an additive effect, whereas Erk1/2 (extracellular signal activated kinase 1/2), p38MAPK, protein phosphatase 1/2A (PP1/2A), and reactive oxygen species (ROS) were not involved. Conclusion: TCDC regulates bile salt transport at the sinusoidal membrane by protein kinase C-and protein phosphatase 2B-mediated retrieval of Ntcp from the plasma membrane. During increased portal bile salt load this mechanism may adjust bile salt uptake along the acinus and protect periportal hepatocytes from harmful bile salt concentrations

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Section: Tcdc Induces Redistribution Of Ntcp In Perfusedmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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“…Mrp2, as well as Bsep and Mdr1, have all been identified in intracellular vesicular structures in addition to the canalicular membrane in rat liver 20,21 . Furthermore, Mrp2 and Bsep are regulated rapidly by retrieval from and/or insertion into the canalicular membrane via intracellular vesicles 21,22,23,24,25 . In support of our finding, a recent study in WIF-B9 cells colocalized apical ABC transporters and Rab11 in polarized cells and restricted these transporters to Rab11-endosomes in non-polarized cells where no canalicular pole was formed 27 .…”

Section: Discussionmentioning

confidence: 99%

Radixin Is Required to Maintain Apical Canalicular Membrane Structure and Function in Rat Hepatocytes

et al. 2006

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“…This is due to a rapid insertion of canalicular transporter molecules, such as the bile salt export pump (Bsep) (50) and the multidrug resistance-related protein (Mrp) 2 (51) into the canalicular membrane. These transporters are stored in subapical vesicles, which can be recruited to the canalicular membrane in response to hepatocyte swelling, whereas hepatocyte shrinkage is cholestatic due to transporter retrieval from the canalicular membrane (21,50,51) . The Src family kinases play an important role in these processes: cell swelling-dependent c-Src activation is involved in osmo-signaling toward transporter insertion into the canalicular membrane and choleresis (18) , whereas hyperosmotic Fyn activation contributes to transporter retrieval and cholestasis (21) .…”

Section: Src Family Kinases and Bile Formationmentioning

confidence: 99%

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

Reinehr

Sommerfeld

Häussinger

2013

BioMolecular Concepts

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Abstract:The Src family kinases Yes, Fyn, and c-Src play a pivotal role in regulating diverse liver functions such as bile flow, proteolysis, apoptosis, and proliferation and are regulated by anisoosmotic cell volume changes, death receptor ligands, and bile acids. For example, cell swelling leads to an integrin-sensed and focal adhesion kinase-mediated activation of c-Src-triggering choleresis, proteolysis inhibition, regulatory volume decrease via p38 MAPK and proliferation via the activation of the epidermal growth factor receptor and extracellular regulated kinases 1 and 2. In contrast, hepatocyte shrinkage generates an almost instantaneous oxidative stress response that triggers the activation of c-Jun N-terminal kinase and the Src family kinases Fyn and Yes. Whereas Fyn activation mediates cholestasis, Yes triggers CD95 activation and apoptosis. This review will discuss the role of Src family kinases in the regulation of liver function with emphasis on their role in osmo-signaling and bile acid signaling.

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Regulation of the dynamic localization of the rat Bsep gene-encoded bile salt export pump by anisoosmolarity

Cited by 83 publications

References 67 publications

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Radixin Is Required to Maintain Apical Canalicular Membrane Structure and Function in Rat Hepatocytes

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

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