Taurolithocholate-induced MRP2 retrieval involves MARCKS phosphorylation by protein kinase Cϵ in HUH-NTCP Cells

Schonhoff, Christopher M.; Webster, Cynthia R. L.; Anwer, Muhammad

doi:10.1002/hep.26333

Cited by 31 publications

(54 citation statements)

References 51 publications

(106 reference statements)

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“…Previous studies have demonstrated that PKC activation can rapidly modulate drug and bile acid transporter location and activity in hepatocytes, by notably promoting their retrieval from sinusoidal or canalicular membranes [49][50][51] or modulating their phosphorylation status [16]. The present study demonstrates that in vitro PKC activation caused by PMA can also result in marked changes in expression of main hepatic drug transporters.…”

Section: Discussionsupporting

confidence: 67%

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati

Vée

Moreau

et al. 2015

Biochemical Pharmacology

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Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-1 or the HNF4 inhibitor BI6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation.

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Section: Discussionsupporting

confidence: 67%

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati

Vée

Moreau

et al. 2015

Biochemical Pharmacology

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“…Another suggested substrate mediating the retrieval of Mrp2 from the membrane is MARCKS, which has been implicated in TLC-induced Mrp2 retrieval, via phosphorylation of MARCKS by PKC« (Schonhoff et al, 2013). The data herein indicate a decrease in membrane-associated phosphorylated MARCKS compared with total membrane MARCKS, with no detection of cytosolic MARCKS.…”

Section: Discussionmentioning

confidence: 54%

“…Mrp2 membrane insertion by PKCa is dependent upon the cooperation of PKA; moreover, Mrp2 insertion is also mediated, in a cAMP-dependent manner, by PKCd (Crocenzi et al, 2008;Park et al, 2012). Membrane retrieval of Mrp2 may also be regulated by novel protein kinases, specifically PKC« or PKCd, when stimulated by cholestatic mediators such as TLC to phosphorylate its substrate, MARCKS (Schonhoff et al, 2013). Mrp2 mislocalization has been reported in both human NASH and the MCD rat model of NASH and may have a profound impact on the proper elimination of xenobiotics (Hardwick et al, , 2012Dzierlenga et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Retrieval of MRP2/Mrp2 has been shown to be stimulated by various oxidative stressors, including lipopolysaccharide, ethacrynic acid, and glutathione depletion (Ji et al, 2004;Sekine et al, 2008Sekine et al, , 2010. Additionally, cholestatic stimuli also induce Mrp2 retrieval from the canalicular membrane, including estradiol-17b-D-glucuronide, taurolithocholate (TLC), and taurochenodeoxycholate (Mottino et al, 2002;Rost et al, 2008;Schonhoff et al, 2013). Conversely, choleretic stimuli such as taurodeoxycholic acid and tauroursodeoxycholic acid can activate Mrp2 insertion back into the canalicular membrane, in a cAMP-regulated process (Beuers et al, 2001;Schonhoff et al, 2008;Wimmer et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…MARCKS, another protein that crosslinks f-actin, has been implicated in the TLC-induced Mrp2 internalization pathway through its phosphorylation by PKC« or PKCd, which stimulates MARCKS membrane retrieval and internalization of Mrp2 (Schonhoff et al, 2013). Rab11, involved in endo-and exocytic processes, is a substrate involved in tauroursodeoxycholic acid (TUDCA)-induced cAMP-mediated translocation of Mrp2 to the canalicular membrane, the disruption of which is associated with cholestasis (Zucchetti et al, 2013;Park et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes

Dzierlenga

Clarke

Cherrington

2016

Drug Metabolism and Disposition

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Interindividual variability in drug response in nonalcoholic steatohepatitis (NASH) can be mediated by altered regulation of drug metabolizing enzymes and transporters. Among these is the mislocalization of multidrug resistance-associated protein (MRP2)/ Mrp2 away from the canalicular membrane, which results in decreased transport of MRP2/Mrp2 substrates. The exact mechanism of this mislocalization is unknown, although increased activation of membrane retrieval processes may be one possibility. The current study measures the activation status of various mediators implicated in the active membrane retrieval or insertion of membrane proteins to identify which processes may be important in rodent methionine and choline deficient diet-induced NASH. The mediators currently known to be associated with transporter mislocalization are stimulated by oxidative stressors and choleretic stimuli, which play a role in the pathogenesis of NASH. The activation of protein kinases PKA, PKCa, PKCd, and PKC« and substrates radixin, myristoylated alanine-rich C-kinase substrate, and Rab11 were measured by comparing the expression, phosphorylation, and membrane translocation between control and NASH. Many of the mediators exhibited altered activation in NASH rats. Consistent with membrane retrieval of Mrp2, NASH rats exhibited a decreased phosphorylation of radixin and increased membrane localization of PKCd and PKC«, thought to be mediators of radixin dephosphorylation. Altered activation of PKCd, PKA, and PKCa may impair the Rab11-mediated active insertion of Mrp2. Overall, these data suggest alterations in membrane retrieval and insertion processes that may contribute to altered localization of membrane proteins in NASH.

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Role of protein kinase C isoforms in bile formation and cholestasis

Anwer

2014

Hepatology

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Transhepatic solute transport provides the osmotic driving force for canalicular bile formation. Choleretic and cholestatic agents affect bile formation, in part, by altering plasma membrane localizations of transporters involved in bile formation. These short-term dynamic changes in transporter location are highly regulated post-translational events requiring various cellular signaling pathways. Interestingly, both choleretic and cholestatic agents activate the same intracellular signaling kinases, such as phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and mitogen activated protein kinase (MAPK). An emerging theme is that choleretic and cholestatic effects may be mediated via different isoforms of these kinases. This is most evident for PKC-mediated regulation of plasma membrane localization of NTCP and MRP2 by conventional PKCα (cPKCα), novel PKCδ (nPKCδ), nPKCε, and atypical PKCζ (aPKCζ). Atypical PKCζ may mediate choleretic effects by inserting NTCP into the plasma membrane and nPKCε may mediate cholestatic effects by retrieving MRP2 from the plasma membrane. On the other hand, cPKCα and nPKCδ may be involved in choleretic, cholestatic and anticholestatic effects by inserting, retrieving and inhibiting retrieval of transporters, respectively. The effects of PKC isoforms may be mediated via phosphorylation of the transporters, actin binding proteins (radixin and MARCKS) and Rab proteins. Human NTCP plays an important role in the entry of hepatitis B and D viruses into hepatocytes and consequent infection. Thus, PKCs by regulating NTCP trafficking may also play an important role in hepatic viral infections.

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Taurolithocholate-induced MRP2 retrieval involves MARCKS phosphorylation by protein kinase Cϵ in HUH-NTCP Cells

Cited by 31 publications

References 51 publications

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes

Role of protein kinase C isoforms in bile formation and cholestasis

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