Short-Term Regulation of Canalicular Transport

Häussinger, Dieter; Schmitt, Marcus; Weiergräber, Oliver H.; Kubitz, Ralf

doi:10.1055/s-2000-9386

Cited by 83 publications

(45 citation statements)

References 103 publications

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“…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%

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: Discussionmentioning

confidence: 99%

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

et al. 2012

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“…Endocytic retrieval of Mrp2 from the canalicular membrane in intracellular compartments contributes, at least in part, to decreased bile flow and Mrp2 transport activity induced by different cholestatic agents (9,14). Because microtubules have been implicated in the trafficking of transporters, we examined the effect of pretreatment with colchicine vs. lumicolchicine on the localization of Mrp2 in the canalicular membrane using two different approaches, confocal immunofluorescence microscopy and Western analysis.…”

Section: Influence Of Colchicine On E 2 -17g-induced Cholestasismentioning

confidence: 99%

Role of microtubules in estradiol-17β-d-glucuronide-induced alteration of canalicular Mrp2 localization and activity

Mottino

Crocenzi²,

Pozzi³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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(E2-17G) induces a marked but reversible inhibition of bile flow in the rat together with endocytic retrieval of multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane to intracellular structures. We analyzed the effect of pretreatment (100 min) with the microtubule inhibitor colchicine or lumicholchicine, its inactive isomer (1 mol/kg iv), on changes in bile flow and localization and function of Mrp2 induced by E2-17G (15 mol/kg iv). Bile flow and biliary excretion of bilirubin, an endogenous Mrp2 substrate, were measured throughout, whereas Mrp2 localization was examined at 20 and 120 min after E2-17G by confocal immunofluorescence microscopy and Western analysis. Colchicine pretreatment alone did not affect bile flow or Mrp2 localization and activity over the short time scale examined (3-4 h). Administration of E2-17G to colchicinepretreated rats induced a marked decrease (85%) in bile flow and biliary excretion of bilirubin as well as internalization of Mrp2 at 20 min. These alterations were of a similar magnitude as in rats pretreated with lumicolchicine followed by E2-17G. Bile flow and Mrp2 localization and activity were restored to control levels within 120 min of E2-17G in animals pretreated with lumicolchicine. In contrast, in colchicine-pretreated rats followed by E2-17G, bile flow and Mrp2 activity remained significantly inhibited by 60%, and confocal and Western studies revealed sustained internalization of Mrp2 120 min after E2-17G. We conclude that recovery from E2-17G cholestasis, associated with exocytic insertion of Mrp2 in the canalicular membrane, but not its initial E2-17G-induced endocytosis, is a microtubule-dependent process. bile secretion; endocytic compartment; colchicine; bilirubin THE MULTIDRUG RESISTANCE-ASSOCIATED protein 2 (Mrp2; Abcc2) mediates the ATP-dependent transport of a wide range of amphiphilic anionic conjugates into bile (5,35

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“…Bile formation is strongly regulated by changes in cell hydration in a way that hepatocyte swelling increases the canalicular secretion of bile acids, whereas hepatocyte shrinkage decreases it [reviewed in (2,46,47) ]. A 10 % increase in the hepatocyte ' s water content doubles the capacity of bile acid excretion into bile (48,49) .…”

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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Short-Term Regulation of Canalicular Transport

Cited by 83 publications

References 103 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

Role of microtubules in estradiol-17β-d-glucuronide-induced alteration of canalicular Mrp2 localization and activity

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

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