p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary
Background & Aims: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21001892 |
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| author | Florian P. Reiter Liangtao Ye Andrea Ofner Tobias S. Schiergens Andreas Ziesch Lydia Brandl Najib Ben Khaled Simon Hohenester Ralf Wimmer Renate Artmann Yulong He Serene M.L. Lee Doris Mayr Changhua Zhang Alexander L. Gerbes Julia Mayerle Gerald Denk Enrico N. De Toni |
| author_facet | Florian P. Reiter Liangtao Ye Andrea Ofner Tobias S. Schiergens Andreas Ziesch Lydia Brandl Najib Ben Khaled Simon Hohenester Ralf Wimmer Renate Artmann Yulong He Serene M.L. Lee Doris Mayr Changhua Zhang Alexander L. Gerbes Julia Mayerle Gerald Denk Enrico N. De Toni |
| author_sort | Florian P. Reiter |
| collection | DOAJ |
| description | Background & Aims: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Approach & Results: Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. Conclusions: We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment. |
| first_indexed | 2024-12-13T18:58:04Z |
| format | Article |
| id | doaj.art-d5c1e3f3e4744b00bcc68fbf2299c769 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-13T18:58:04Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-d5c1e3f3e4744b00bcc68fbf2299c7692022-12-21T23:34:45ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-0113195112p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummaryFlorian P. Reiter0Liangtao Ye1Andrea Ofner2Tobias S. Schiergens3Andreas Ziesch4Lydia Brandl5Najib Ben Khaled6Simon Hohenester7Ralf Wimmer8Renate Artmann9Yulong He10Serene M.L. Lee11Doris Mayr12Changhua Zhang13Alexander L. Gerbes14Julia Mayerle15Gerald Denk16Enrico N. De Toni17Department of Medicine II, University Hospital, LMU Munich, Munich, Germany; Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany; Liver Center, University Hospital, LMU Munich, Munich, Germany; Correspondence Address correspondence to: Florian P. Reiter, MD, Department of Medicine II, Liver Center Munich, University of Munich, Marchioninistraße 15, D-81377 Munich, Germany. fax: +49-931-201-640023.Department of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, Germany; Center for Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, ChinaDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyDepartment of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany; Biobank of the Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyInstitute of Pathology, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyCenter for Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, ChinaDepartment of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany; Biobank of the Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, GermanyInstitute of Pathology, LMU Munich, Munich, GermanyCenter for Digestive Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, ChinaDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, Germany; Transplantation Center Munich, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany; Liver Center, University Hospital, LMU Munich, Munich, GermanyBackground & Aims: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Approach & Results: Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. Conclusions: We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.http://www.sciencedirect.com/science/article/pii/S2352345X21001892FibrosisCirrhosisChronic Liver DiseaseTransforming Growth Factor-βPlatelet-Derived Growth Factor BB |
| spellingShingle | Florian P. Reiter Liangtao Ye Andrea Ofner Tobias S. Schiergens Andreas Ziesch Lydia Brandl Najib Ben Khaled Simon Hohenester Ralf Wimmer Renate Artmann Yulong He Serene M.L. Lee Doris Mayr Changhua Zhang Alexander L. Gerbes Julia Mayerle Gerald Denk Enrico N. De Toni p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary Cellular and Molecular Gastroenterology and Hepatology Fibrosis Cirrhosis Chronic Liver Disease Transforming Growth Factor-β Platelet-Derived Growth Factor BB |
| title | p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary |
| title_full | p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary |
| title_fullStr | p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary |
| title_full_unstemmed | p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary |
| title_short | p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary |
| title_sort | p70 ribosomal protein s6 kinase is a checkpoint of human hepatic stellate cell activation and liver fibrosis in micesummary |
| topic | Fibrosis Cirrhosis Chronic Liver Disease Transforming Growth Factor-β Platelet-Derived Growth Factor BB |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21001892 |
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