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G‐protein‐coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß‐d‐glucuronide‐induced cholestasis

Zucchetti, Andrés E. ; Barosso, Ismael R. ; Boaglio, Andrea C. ; Basiglio, Cecilia L. ; Miszczuk, Gisel ; Larocca, M. Cecilia ; Ruiz, M. Laura ; Davio, Carlos A. ; Roma, Marcelo G. ; Crocenzi, Fernando A. ; Pozzi, Enrique J. Sánchez

Hepatology (Baltimore, Md.), 2014-03, Vol.59 (3), p.1016-1029 [Periódico revisado por pares]

United States: Wiley Subscription Services, Inc

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Título:
G‐protein‐coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß‐d‐glucuronide‐induced cholestasis
Autor: Zucchetti, Andrés E. ; Barosso, Ismael R. ; Boaglio, Andrea C. ; Basiglio, Cecilia L. ; Miszczuk, Gisel ; Larocca, M. Cecilia ; Ruiz, M. Laura ; Davio, Carlos A. ; Roma, Marcelo G. ; Crocenzi, Fernando A. ; Pozzi, Enrique J. Sánchez
Assuntos: Adenylyl Cyclases - metabolism ; Animals ; ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP-Binding Cassette Transporters - metabolism ; Bile Canaliculi - metabolism ; Cells, Cultured ; Cholestasis - chemically induced ; Cholestasis - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Estradiol - analogs & derivatives ; Estradiol - toxicity ; Gene Knockdown Techniques ; Hepatocytes - cytology ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Hepatology ; Rats ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Signal Transduction - drug effects ; Signal Transduction - physiology
É parte de: Hepatology (Baltimore, Md.), 2014-03, Vol.59 (3), p.1016-1029
Notas: Potential conflict of interest: Nothing to report.
This work was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica (PICTs 2006 no. 02012 and 2010 no. 1197) and Consejo Nacional de Investigaciones Cientificas y Técnicas (PIP 0691).
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Descrição: Estradiol‐17ß‐d‐glucuronide (E17G) activates different signaling pathways (e.g., Ca2+‐dependent protein kinase C, phosphoinositide 3‐kinase/protein kinase B, mitogen‐activated protein kinases [MAPKs] p38 and extracellular signal‐related kinase 1/2, and estrogen receptor alpha) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters, bile salt export pump (Abcb11) and multidrug resistance‐associated protein 2 (Abcc2). E17G shares with nonconjugated estradiol the capacity to activate these pathways. G‐protein‐coupled receptor 30 (GPR30) is a receptor implicated in nongenomic effects of estradiol, and the aim of this study was to analyze the potential role of this receptor and its downstream effectors in E17G‐induced cholestasis. In vitro, GPR30 inhibition by G15 or its knockdown with small interfering RNA strongly prevented E17G‐induced impairment of canalicular transporter function and localization. E17G increased cyclic adenosine monophosphate (cAMP) levels, and this increase was blocked by G15, linking GPR30 to adenylyl cyclase (AC). Moreover, AC inhibition totally prevented E17G insult. E17G also increased protein kinase A (PKA) activity, which was blocked by G15 and AC inhibitors, connecting the links of the pathway, GPR30‐AC‐PKA. PKA inhibition prevented E17G‐induced cholestasis, whereas exchange protein activated directly by cyclic nucleotide/MAPK kinase, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of the GPR30‐AC‐PKA pathway totally prevented E17G‐induced alteration in Abcb11 and Abcc2 function and localization. Conclusion: Activation of GPR30‐AC‐PKA is a key factor in the alteration of canalicular transporter function and localization induced by E17G. Interaction of E17G with GPR30 may be the first event in the cascade of signaling activation. (Hepatology 2014;59:1016–1029)
Editor: United States: Wiley Subscription Services, Inc
Idioma: Inglês

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G‐protein‐coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß‐d‐glucuronide‐induced cholestasis

Zucchetti, Andrés E. ; Barosso, Ismael R. ; Boaglio, Andrea C. ; Basiglio, Cecilia L. ; Miszczuk, Gisel ; Larocca, M. Cecilia ; Ruiz, M. Laura ; Davio, Carlos A. ; Roma, Marcelo G. ; Crocenzi, Fernando A. ; Pozzi, Enrique J. Sánchez

United States: Wiley Subscription Services, Inc

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