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Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis
Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion–transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784341/ https://www.ncbi.nlm.nih.gov/pubmed/34971708 http://dx.doi.org/10.1016/j.jbc.2021.101543 |
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author | Li, Mingqiao Wang, Weihua Cheng, Ying Zhang, Xiaoxun Zhao, Nan Tan, Ya Xie, Qiaoling Chai, Jin Pan, Qiong |
author_facet | Li, Mingqiao Wang, Weihua Cheng, Ying Zhang, Xiaoxun Zhao, Nan Tan, Ya Xie, Qiaoling Chai, Jin Pan, Qiong |
author_sort | Li, Mingqiao |
collection | PubMed |
description | Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion–transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor fibroblast growth factor 19 and inflammatory mediator tumor necrosis factor α (TNFα) increased OATP3A1 mRNA levels in hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in cholestasis is unknown. To address this, we collected plasma samples from control and obstructive cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1 mRNA transcripts in patients with obstructive cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and extracellular signal–regulated kinase (ERK) signaling pathways as well as expression of related transcription factors p65 and specificity protein 1 (SP1). Dual-luciferase reporter and chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors BAY11-7082 and PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive cholestasis by activating NF-κB p65 and ERK–SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK–SP1 signaling may be a potential target to ameliorate cholestasis-associated liver injury. |
format | Online Article Text |
id | pubmed-8784341 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-87843412022-01-31 Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis Li, Mingqiao Wang, Weihua Cheng, Ying Zhang, Xiaoxun Zhao, Nan Tan, Ya Xie, Qiaoling Chai, Jin Pan, Qiong J Biol Chem Research Article Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion–transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor fibroblast growth factor 19 and inflammatory mediator tumor necrosis factor α (TNFα) increased OATP3A1 mRNA levels in hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in cholestasis is unknown. To address this, we collected plasma samples from control and obstructive cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1 mRNA transcripts in patients with obstructive cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and extracellular signal–regulated kinase (ERK) signaling pathways as well as expression of related transcription factors p65 and specificity protein 1 (SP1). Dual-luciferase reporter and chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors BAY11-7082 and PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive cholestasis by activating NF-κB p65 and ERK–SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK–SP1 signaling may be a potential target to ameliorate cholestasis-associated liver injury. American Society for Biochemistry and Molecular Biology 2021-12-29 /pmc/articles/PMC8784341/ /pubmed/34971708 http://dx.doi.org/10.1016/j.jbc.2021.101543 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Li, Mingqiao Wang, Weihua Cheng, Ying Zhang, Xiaoxun Zhao, Nan Tan, Ya Xie, Qiaoling Chai, Jin Pan, Qiong Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis |
title | Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis |
title_full | Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis |
title_fullStr | Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis |
title_full_unstemmed | Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis |
title_short | Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis |
title_sort | tumor necrosis factor α upregulates the bile acid efflux transporter oatp3a1 via multiple signaling pathways in cholestasis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784341/ https://www.ncbi.nlm.nih.gov/pubmed/34971708 http://dx.doi.org/10.1016/j.jbc.2021.101543 |
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