Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate

Sommerfeld, Annika; Mayer, P; Cantore, Miriam; Häussinger, Dieter

doi:10.1074/jbc.m115.666883

Cited by 15 publications

(35 citation statements)

References 79 publications

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“…This is due to a TUDCinduced RGD peptide-sensitive generation of cyclic adenosine monophosphate (cAMP) [25] . In line with this, like TUDC cAMP also prevents hyperosmotic Fyn activation [26,27] .…”

Section: Mapksupporting

confidence: 66%

“…1 ). As also shown in figure 1 , perfusion of the rat liver with hyperosmotic medium results in Bsep retrieval from the canalicular membrane, and this effect can completely be reversed by TUDC, which leads to Bsep re-insertion [26,27] . This process is sensitive to the RGD peptide [26,27] .…”

Section: Mapkmentioning

confidence: 69%

“…2 ). As shown in figure 2 , hyperosmolarity triggers the internalization of Ntcp and this is reversed by TUDC, whereas hyperosmolarity and TUDC have no effect on the fluorescence profile of Na + /K + -ATPase [26,27] . Also TUDC-induced Ntcp reinsertion into the basolateral membrane is mediated by a TUDCinduced β 1 -integrin activation, which results in an inhibition of the Src family kinase Fyn.…”

Section: Mapkmentioning

confidence: 95%

“…Hyperosmotic hepatocyte shrinkage not only triggers Mrp2 and Bsep retrieval from the canalicular membrane [21,22,26,27] but also retrieves Ntcp from the basolateral membrane in a Fyn-dependent way [26,27] , whereas hepatocyte swelling triggers Ntcp insertion [28] . Ntcp internalization/reinsertion can be investigated by measuring fluorescence intensity profiles perpendicular to the plasma membrane after immunostaining of Ntcp and Na fig.…”

Section: Mapkmentioning

confidence: 99%

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Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection

Häussinger

Kordes²

2017

Dig Dis

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Ursodeoxycholate and its taurine conjugate tauroursodeoxycholate (TUDC) promote choleresis by triggering the insertion of transport proteins for bile acids into the canalicular and basolateral membranes of hepatocytes. In addition, TUDC exerts hepatoprotective and anti-apoptotic effects, can counteract the action of toxic bile acids and reduce endoplasmic reticulum stress. TUDC can also initiate the differentiation of multipotent mesenchymal stem cells (MSC) including hepatic stellate cells and promote their development into hepatocyte-like cells. Although the hepatoprotective and choleretic action of TUDC is empirically used in clinical medicine since decades, the underlying molecular mechanisms remained largely unclear. Since TUDC has little or no potency to activate known bile acid receptors, such as farnesoid X receptor and transmembrane G protein-coupled bile acid receptor, other receptors must be involved in TUDC-mediated signaling. Recent research demonstrates that integrins serve as sensors for TUDC. After binding of TUDC to α₅β₁-integrin, the β₁-integrin subunit becomes activated through a conformational change, thereby triggering integrin signaling with the downstream activation of focal adhesion kinase, c-Src, the epidermal growth factor receptor and activation of the mitogen-activated protein kinases, Erks and p38. These events trigger choleresis through a coordinated insertion of the sodium-taurocholate cotransporting polypeptide into the basolateral membrane and of the bile salt export pump into the canalicular membrane. In addition to its choleretic action, TUDC-induced integrin activation triggers a cyclic adenosine monophosphate-dependent protein kinase A activation in hepatocytes, which provides the basis for the anti-apoptotic effect of TUDC. On the other hand, the TUDC-induced stimulation of MSC differentiation appears not to be mediated by integrins. This article gives a brief overview about our work on the signaling network-mediating hepatoprotection by TUDC.

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Section: Mapksupporting

confidence: 66%

Section: Mapkmentioning

confidence: 69%

Section: Mapkmentioning

confidence: 95%

Section: Mapkmentioning

confidence: 99%

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Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection

Häussinger

Kordes²

2017

Dig Dis

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“…The high sensitivity of intracellular bile acid concentration to BSEP activity as shown in our model and in the DILIsym model can explain the large variation in sensitivity for cholestatic drug effects in the human population. The value found for NTCP of 5.9 fmol/μg plasma membrane protein might have been an overestimation of active transporter as it is higher than found by others (Qiu et al, 2013;Wang et al, 2015) and it has been reported that the transporter can be also found in submembrane vesicles (Sommerfeld et al, 2015;Webster et al, 2002). The role of OATPs in the uptake of bile acids was assumed to be low, but this should be incorporated in a future version of the model.…”

Section: S Notenboom Et Almentioning

confidence: 82%

Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

Notenboom

Weigand

Proost

et al. 2018

European Journal of Pharmaceutical Sciences

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A B S T R A C TDrug-induced liver injury (DILI) is a common reason for drug withdrawal from the market. An important cause of DILI is drug-induced cholestasis. One of the major players involved in drug-induced cholestasis is the bile salt efflux pump (BSEP; ABCB11). Inhibition of BSEP by drugs potentially leads to cholestasis due to increased (toxic) intrahepatic concentrations of bile acids with subsequent cell injury. In order to investigate the possibilities for in silico prediction of cholestatic effects of drugs, we developed a mechanistic biokinetic model for human liver bile acid handling populated with human in vitro data. For this purpose we considered nine groups of bile acids in the human bile acid pool, i.e. chenodeoxycholic acid, deoxycholic acid, the remaining unconjugated bile acids and the glycine and taurine conjugates of each of the three groups. Michaelis-Menten kinetics of the human uptake transporter Na + -taurocholate cotransporting polypeptide (NTCP; SLC10A1) and BSEP were measured using NTCP-transduced HEK293 cells and membrane vesicles from BSEP-overexpressing HEK293 cells. For in vitro-in vivo scaling, transporter abundance was determined by LC-MS/MS in these HEK293 cells and vesicles as well as in human liver tissue. Other relevant human kinetic parameters were collected from literature, such as portal bile acid levels and composition, bile acid synthesis and amidation rate. Additional empirical scaling was applied by increasing the excretion rate with a factor 2.4 to reach near physiological steady-state intracellular bile acid concentrations (80 μM) after exposure to portal vein bile acid levels. Simulations showed that intracellular bile acid concentrations increase 1.7 fold in the presence of the BSEP inhibitors and cholestatic drugs cyclosporin A or glibenclamide, at intrahepatic concentrations of 6.6 and 20 μM, respectively. This simplified model provides a tool for a first indication whether drugs at therapeutic concentrations might cause cholestasis by inhibiting BSEP.

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Loops and layers of post-translational modifications of drug transporters

You

2017

Advanced Drug Delivery Reviews

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Drug transporters encoded by solute carrier (SLC) family are distributed in multiple organs including kidney, liver, placenta, brain, and intestine, where they mediate the absorption, distribution, and excretion of a diverse array of environmental toxins and clinically important drugs. Alterations in the expression and function of these transporters play important roles in intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs. Consequently, the activity of these transporters must be highly regulated so as to carry out their normal functions. While it is clear that the regulation of these transporters tightly depends on genetic mechanisms, many studies have demonstrated that these transporters are the target of various post-translational modifications. This review article summarizes the recent advances in identifying the posttranslational modifications underlying the regulation of the drug transporters of SLC family. Such mechanisms are pivotal not only in physiological conditions, but also in diseases.

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Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate

Abstract: Background:Little is known about the effect of hyperosmotic hepatocyte shrinkage on Na ϩ -taurocholate cotransporting

Cited by 15 publications

References 79 publications

Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection

Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection

Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

Loops and layers of post-translational modifications of drug transporters

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