Abstract | BACKGROUND & AIMS: 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.
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Authors | 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 |
Journal | Cellular and molecular gastroenterology and hepatology
(Cell Mol Gastroenterol Hepatol)
Vol. 13
Issue 1
Pg. 95-112
( 2022)
ISSN: 2352-345X [Electronic] United States |
PMID | 34537439
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Ribosomal Protein S6 Kinases, 70-kDa
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Topics |
- Animals
- Cell Proliferation
- Hepatic Stellate Cells
(pathology)
- Humans
- Liver Cirrhosis
(genetics)
- Mice
- Ribosomal Protein S6 Kinases, 70-kDa
(metabolism, therapeutic use)
- Signal Transduction
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