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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Fibrosis Cirrhosis Chronic Liver Disease Transforming Growth Factor-β Platelet-Derived Growth Factor BB Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/d5c1e3f3e4744b00bcc68fbf2299c769
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spelling	oai:doaj.org-article:d5c1e3f3e4744b00bcc68fbf2299c7692021-11-14T04:34:18Zp70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary2352-345X10.1016/j.jcmgh.2021.09.001https://doaj.org/article/d5c1e3f3e4744b00bcc68fbf2299c7692022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001892https://doaj.org/toc/2352-345XBackground & 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.Florian P. ReiterLiangtao YeAndrea OfnerTobias S. SchiergensAndreas ZieschLydia BrandlNajib Ben KhaledSimon HohenesterRalf WimmerRenate ArtmannYulong HeSerene M.L. LeeDoris MayrChanghua ZhangAlexander L. GerbesJulia MayerleGerald DenkEnrico N. De ToniElsevierarticleFibrosisCirrhosisChronic Liver DiseaseTransforming Growth Factor-βPlatelet-Derived Growth Factor BBDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 95-112 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fibrosis Cirrhosis Chronic Liver Disease Transforming Growth Factor-β Platelet-Derived Growth Factor BB Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Fibrosis Cirrhosis Chronic Liver Disease Transforming Growth Factor-β Platelet-Derived Growth Factor BB Diseases of the digestive system. Gastroenterology RC799-869 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
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.
format	article
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
title	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_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_sort	p70 ribosomal protein s6 kinase is a checkpoint of human hepatic stellate cell activation and liver fibrosis in micesummary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/d5c1e3f3e4744b00bcc68fbf2299c769
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p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary

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