Hormonal Modulation of Hepatic cAMP Prevents Estradiol 17β-d-Glucuronide-Induced Cholestasis in Perfused Rat Liver

Zucchetti, Andrés E.; Barosso, Ismael Ricardo; Boaglio, Andrea Carolina; Luquita, Marcelo G.; Roma, Marcelo G.; Crocenzi, Fernando A.; Pozzi, Enrique J. Sánchez

doi:10.1007/s10620-013-2558-4

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…TUDCA-induced Mrp2 retrieval was shown to be mediated by Rab11; furthermore, Mrp2 and other transporters are known to be shuttled between the membrane and Rab11-positive endosomes. Processes impacting Rab11 activation are likely to result in the misregulation of bile salt export pump as well (Zucchetti et al, 2013). Our data indicate a decreased expression of Rab11, which could indicate a global dysregulation of endocytic processes in NASH, impacting more than transporters alone.…”

Section: Discussionmentioning

confidence: 74%

“…Rab11 is a vesicular transport mediator, which is required for transgolgi-to-plasma-membrane shuttling, and as another regulator of Mrp2 localization, it is more directly implicated in active endocytosis/ exocytosis (Chen et al, 1998;Zucchetti et al, 2013;Park et al, 2014). TUDCA-induced Mrp2 retrieval was shown to be mediated by Rab11; furthermore, Mrp2 and other transporters are known to be shuttled between the membrane and Rab11-positive endosomes.…”

Section: Discussionmentioning

confidence: 99%

“…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). Two potential mediators of this process are PKCd, which regulates Mrp2 membrane insertion via kinase activity, and the calcium-dependent PKA/PKCa pathway, which increases total biliary secretion (Wimmer et al, 2008;Park et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes

Dzierlenga

Clarke

Cherrington

2016

Drug Metabolism and Disposition

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“…cAMP and tauroursodeoxycholate-induced MRP2 membrane insertion has been shown to involve Rab11 specifically, over other isoforms (28). Interestingly, Rab11 is also involved in BSEP translocation, suggesting an overlap in transport regulatory mechanisms (40). …”

Section: Discussionmentioning

confidence: 99%

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis

Dzierlenga

Cherrington

2018

J Biochem & Molecular Tox

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Nonalcoholic steatohepatitis (NASH) remodels the expression and function of genes and proteins that are critical for drug disposition. This study sought to determine whether disruption of membrane protein trafficking pathways in human NASH contributes to altered localization of multidrug resistance-associated protein 2 (MRP2). A comprehensive immunoblot analysis assessed the phosphorylation, membrane translocation, and expression of transporter membrane insertion regulators, including several protein kinases (PK), radixin, MARCKS, and Rab11. Radixin exhibited a decreased phosphorylation and total expression, whereas Rab11 had an increased membrane localization. PKCδ, PKCα, and PKA had increased membrane activation, whereas PKCε had a decreased phosphorylation and membrane expression. Radixin dephosphorylation may activate MRP2 membrane retrieval in NASH; however, the activation of Rab11/PKCδ and PKA/PKCα suggest an activation of membrane insertion pathways as well. Overall these data suggest an altered regulation of protein trafficking in human NASH, although other processes may be involved in the regulation of MRP2 localization.

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“…Mechanistically, salbutamol/EPAC promotes a microtubule-dependent and long-range trafficking of Abcb11/Abcc2-containing vesicles, whereas glucagon/ PKA modulates the microfilament-mediated fusion of these vesicles with the apical membrane (1217). In a follow-up study, the preventive effects of salbutamol and glucagon were further validated in more physiological settings using perfused rat liver and in vivo alanine administration, which induces pancreatic glucagon secretion (1218).…”

Section: Epac Proteins and Hepatic Functionsmentioning

confidence: 96%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

163

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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Hormonal Modulation of Hepatic cAMP Prevents Estradiol 17β-d-Glucuronide-Induced Cholestasis in Perfused Rat Liver

Cited by 13 publications

References 33 publications

Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes

Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

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