Cargando…
Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate
Taurolithocholate (TLC) produces cholestasis by inhibiting biliary solute secretion in part by retrieving MRP2 from the plasma membrane (PM). Tauroursodeoxycholate (TUDC) and cAMP reverse TLC‐induced cholestasis by inhibiting TLC‐induced retrieval of MRP2. However, cellular mechanisms for this rever...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727282/ https://www.ncbi.nlm.nih.gov/pubmed/29192063 http://dx.doi.org/10.14814/phy2.13529 |
_version_ | 1783285848258641920 |
---|---|
author | Park, Se Won Webster, Cynthia R. L. Anwer, Mohammed S. |
author_facet | Park, Se Won Webster, Cynthia R. L. Anwer, Mohammed S. |
author_sort | Park, Se Won |
collection | PubMed |
description | Taurolithocholate (TLC) produces cholestasis by inhibiting biliary solute secretion in part by retrieving MRP2 from the plasma membrane (PM). Tauroursodeoxycholate (TUDC) and cAMP reverse TLC‐induced cholestasis by inhibiting TLC‐induced retrieval of MRP2. However, cellular mechanisms for this reversal are incompletely understood. Recently, we reported that TLC decreases PM‐MRP2 by activating PKCε followed by phosphorylation of myristoylated alanine‐rich C kinase substrate (MARCKS). Thus, cAMP and TUDC may reverse TLC‐induced cholestasis by inhibiting the TLC/PKC ε/MARCKS phosphorylation pathway. We tested this hypothesis by determining whether TUDC and/or cAMP inhibit TLC‐induced activation of PKCε and phosphorylation of MARCKS. Studies were conducted in HuH‐NTCP cell line and rat hepatocytes. Activation of PKC ε was determined from the translocation of PKC ε to PM using a biotinylation method. Phosphorylation of MARCKS was determined by immunoblotting with a phospho‐MARCKS antibody. TLC, but not cAMP and TUDC, activated PKC ε and increased MARCKS phosphorylation in HuH‐NTCP as well in rat hepatocytes. Treatment with TUDC or cAMP inhibited TLC‐induced activation of PKCε and increases in MARCKS phosphorylation in both cell types. Based on these results, we conclude that the reversal of TLC‐induced cholestasis by cAMP and TUDC involves, at least in part, inhibition of TLC‐mediated activation of the PKCε/MARCKS phosphorylation pathway. |
format | Online Article Text |
id | pubmed-5727282 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57272822017-12-13 Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate Park, Se Won Webster, Cynthia R. L. Anwer, Mohammed S. Physiol Rep Original Research Taurolithocholate (TLC) produces cholestasis by inhibiting biliary solute secretion in part by retrieving MRP2 from the plasma membrane (PM). Tauroursodeoxycholate (TUDC) and cAMP reverse TLC‐induced cholestasis by inhibiting TLC‐induced retrieval of MRP2. However, cellular mechanisms for this reversal are incompletely understood. Recently, we reported that TLC decreases PM‐MRP2 by activating PKCε followed by phosphorylation of myristoylated alanine‐rich C kinase substrate (MARCKS). Thus, cAMP and TUDC may reverse TLC‐induced cholestasis by inhibiting the TLC/PKC ε/MARCKS phosphorylation pathway. We tested this hypothesis by determining whether TUDC and/or cAMP inhibit TLC‐induced activation of PKCε and phosphorylation of MARCKS. Studies were conducted in HuH‐NTCP cell line and rat hepatocytes. Activation of PKC ε was determined from the translocation of PKC ε to PM using a biotinylation method. Phosphorylation of MARCKS was determined by immunoblotting with a phospho‐MARCKS antibody. TLC, but not cAMP and TUDC, activated PKC ε and increased MARCKS phosphorylation in HuH‐NTCP as well in rat hepatocytes. Treatment with TUDC or cAMP inhibited TLC‐induced activation of PKCε and increases in MARCKS phosphorylation in both cell types. Based on these results, we conclude that the reversal of TLC‐induced cholestasis by cAMP and TUDC involves, at least in part, inhibition of TLC‐mediated activation of the PKCε/MARCKS phosphorylation pathway. John Wiley and Sons Inc. 2017-11-30 /pmc/articles/PMC5727282/ /pubmed/29192063 http://dx.doi.org/10.14814/phy2.13529 Text en © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Park, Se Won Webster, Cynthia R. L. Anwer, Mohammed S. Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate |
title | Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate |
title_full | Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate |
title_fullStr | Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate |
title_full_unstemmed | Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate |
title_short | Mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate |
title_sort | mechanism of inhibition of taurolithocholate‐induced retrieval of plasma membrane mrp2 by cyclic amp and tauroursodeoxycholate |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727282/ https://www.ncbi.nlm.nih.gov/pubmed/29192063 http://dx.doi.org/10.14814/phy2.13529 |
work_keys_str_mv | AT parksewon mechanismofinhibitionoftaurolithocholateinducedretrievalofplasmamembranemrp2bycyclicampandtauroursodeoxycholate AT webstercynthiarl mechanismofinhibitionoftaurolithocholateinducedretrievalofplasmamembranemrp2bycyclicampandtauroursodeoxycholate AT anwermohammeds mechanismofinhibitionoftaurolithocholateinducedretrievalofplasmamembranemrp2bycyclicampandtauroursodeoxycholate |