The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells
Abstract Cholestatic liver diseases, accompanied by the hepatic accumulation of bile salts, frequently lead to liver fibrosis, while underlying profibrogenic mechanisms remain incompletely understood. Here, we evaluated the role of extracellular pH (pHe) on bile salt entry and hepatic stellate cell...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07192-4 |
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| author | Jingguo Li Shun Yao Sebastian Zimny Dennis Koob Hai Jin Ralf Wimmer Gerald Denk Biguang Tuo Simon Hohenester |
| author_facet | Jingguo Li Shun Yao Sebastian Zimny Dennis Koob Hai Jin Ralf Wimmer Gerald Denk Biguang Tuo Simon Hohenester |
| author_sort | Jingguo Li |
| collection | DOAJ |
| description | Abstract Cholestatic liver diseases, accompanied by the hepatic accumulation of bile salts, frequently lead to liver fibrosis, while underlying profibrogenic mechanisms remain incompletely understood. Here, we evaluated the role of extracellular pH (pHe) on bile salt entry and hepatic stellate cell (HSC) activation and proliferation. As modulators of intracellular pH (pHi), various proton pump inhibitors (PPI) were tested for their ability to prevent bile salt entry and HSC activation. Lastly, the PPI pantoprazole was employed in the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-diet model of cholestatic liver fibrosis. We found in vitro, that slightly acidic pHe (7.2–7.3) enhanced bile salt accumulation in HSC and was a prerequisite to bile salt-induced HSC activation. Pantoprazole in the DDC model exhibited antifibrotic effects. We conclude that bile salt-induced activation of HSC may depend on the slightly acidic microenvironment present in the perisinusoidal space and modulation of pHi in HSC may offer a novel pharmacological target in cholestatic disease. |
| format | Article |
| id | doaj-art-1e73f61c54c7464294c0ea8f99f2fdd8 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-1e73f61c54c7464294c0ea8f99f2fdd82024-12-01T12:40:32ZengNature PortfolioCommunications Biology2399-36422024-11-017111410.1038/s42003-024-07192-4The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cellsJingguo Li0Shun Yao1Sebastian Zimny2Dennis Koob3Hai Jin4Ralf Wimmer5Gerald Denk6Biguang Tuo7Simon Hohenester8Department of Medicine II, LMU University Hospital, LMU MunichDepartment of Gastroenterology, Affiliated Hospital of Zunyi Medical UniversityDepartment of Medicine II, LMU University Hospital, LMU MunichDepartment of Medicine II, LMU University Hospital, LMU MunichDepartment of Gastroenterology, Affiliated Hospital of Zunyi Medical UniversityDepartment of Medicine II, LMU University Hospital, LMU MunichDepartment of Medicine II, LMU University Hospital, LMU MunichDepartment of Gastroenterology, Affiliated Hospital of Zunyi Medical UniversityDepartment of Medicine II, LMU University Hospital, LMU MunichAbstract Cholestatic liver diseases, accompanied by the hepatic accumulation of bile salts, frequently lead to liver fibrosis, while underlying profibrogenic mechanisms remain incompletely understood. Here, we evaluated the role of extracellular pH (pHe) on bile salt entry and hepatic stellate cell (HSC) activation and proliferation. As modulators of intracellular pH (pHi), various proton pump inhibitors (PPI) were tested for their ability to prevent bile salt entry and HSC activation. Lastly, the PPI pantoprazole was employed in the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-diet model of cholestatic liver fibrosis. We found in vitro, that slightly acidic pHe (7.2–7.3) enhanced bile salt accumulation in HSC and was a prerequisite to bile salt-induced HSC activation. Pantoprazole in the DDC model exhibited antifibrotic effects. We conclude that bile salt-induced activation of HSC may depend on the slightly acidic microenvironment present in the perisinusoidal space and modulation of pHi in HSC may offer a novel pharmacological target in cholestatic disease.https://doi.org/10.1038/s42003-024-07192-4 |
| spellingShingle | Jingguo Li Shun Yao Sebastian Zimny Dennis Koob Hai Jin Ralf Wimmer Gerald Denk Biguang Tuo Simon Hohenester The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells Communications Biology |
| title | The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells |
| title_full | The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells |
| title_fullStr | The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells |
| title_full_unstemmed | The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells |
| title_short | The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells |
| title_sort | acidic microenvironment in the perisinusoidal space critically determines bile salt induced activation of hepatic stellate cells |
| url | https://doi.org/10.1038/s42003-024-07192-4 |
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