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Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex
Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206975/ https://www.ncbi.nlm.nih.gov/pubmed/31930324 http://dx.doi.org/10.1093/intimm/dxaa002 |
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author | Rao, Jianhua Yang, Chao Yang, Shikun Lu, Hao Hu, Yuanchang Lu, Ling Cheng, Feng Wang, Xuehao |
author_facet | Rao, Jianhua Yang, Chao Yang, Shikun Lu, Hao Hu, Yuanchang Lu, Ling Cheng, Feng Wang, Xuehao |
author_sort | Rao, Jianhua |
collection | PubMed |
description | Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5(−/−)) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5(−/−) bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5(−/−) macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5(−/−) BMDMs. Notably, expression of β-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3β to repress the interaction between Gsk3β and β-catenin, thus disrupting the β-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated β-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5(−/−) BMDMs. From a therapeutic perspective, TGR5(−/−) BMDM administration aggravated BDL-induced CHI, which was effectively rescued by β-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the β-catenin destruction complex, with therapeutic implications for the management of human CHI. |
format | Online Article Text |
id | pubmed-7206975 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72069752020-05-13 Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex Rao, Jianhua Yang, Chao Yang, Shikun Lu, Hao Hu, Yuanchang Lu, Ling Cheng, Feng Wang, Xuehao Int Immunol Original Research Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5(−/−)) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5(−/−) bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5(−/−) macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5(−/−) BMDMs. Notably, expression of β-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3β to repress the interaction between Gsk3β and β-catenin, thus disrupting the β-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated β-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5(−/−) BMDMs. From a therapeutic perspective, TGR5(−/−) BMDM administration aggravated BDL-induced CHI, which was effectively rescued by β-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the β-catenin destruction complex, with therapeutic implications for the management of human CHI. Oxford University Press 2020-01-13 /pmc/articles/PMC7206975/ /pubmed/31930324 http://dx.doi.org/10.1093/intimm/dxaa002 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Society for Immunology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Research Rao, Jianhua Yang, Chao Yang, Shikun Lu, Hao Hu, Yuanchang Lu, Ling Cheng, Feng Wang, Xuehao Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex |
title | Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by
stabilizing the β-catenin destruction complex |
title_full | Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by
stabilizing the β-catenin destruction complex |
title_fullStr | Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by
stabilizing the β-catenin destruction complex |
title_full_unstemmed | Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by
stabilizing the β-catenin destruction complex |
title_short | Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by
stabilizing the β-catenin destruction complex |
title_sort | deficiency of tgr5 exacerbates immune-mediated cholestatic hepatic injury by
stabilizing the β-catenin destruction complex |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206975/ https://www.ncbi.nlm.nih.gov/pubmed/31930324 http://dx.doi.org/10.1093/intimm/dxaa002 |
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