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Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation
Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260902/ https://www.ncbi.nlm.nih.gov/pubmed/27831566 http://dx.doi.org/10.1038/cddis.2016.368 |
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author | de Mingo, Álvaro de Gregorio, Estefanía Moles, Anna Tarrats, Núria Tutusaus, Anna Colell, Anna Fernandez-Checa, Jose C Morales, Albert Marí, Montserrat |
author_facet | de Mingo, Álvaro de Gregorio, Estefanía Moles, Anna Tarrats, Núria Tutusaus, Anna Colell, Anna Fernandez-Checa, Jose C Morales, Albert Marí, Montserrat |
author_sort | de Mingo, Álvaro |
collection | PubMed |
description | Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the roles of CTSB/S and SIRT1 in the regulation of hepatic inflammation using primary parenchymal and non-parenchymal hepatic cell types and cell lines. In all cells analyzed, CTSB/S inhibition reduces nuclear p65-NF-κB and κB-dependent gene expression after LPS or TNF through enhanced SIRT1 expression. Accordingly, SIRT1 silencing was sufficient to enhance inflammatory gene expression. Importantly, in a dietary mouse model of non-alcoholic steatohepatitis, or in healthy and fibrotic mice after LPS challenge, cathepsins as well as NF-κB-dependent gene expression are activated. Consistent with the prominent role of cathepsin/SIRT1, cysteine cathepsin inhibition limits NF-κB-dependent hepatic inflammation through the regulation of SIRT1 in all in vivo settings, providing a novel anti-inflammatory therapeutic target in liver disease. |
format | Online Article Text |
id | pubmed-5260902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-52609022017-01-26 Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation de Mingo, Álvaro de Gregorio, Estefanía Moles, Anna Tarrats, Núria Tutusaus, Anna Colell, Anna Fernandez-Checa, Jose C Morales, Albert Marí, Montserrat Cell Death Dis Original Article Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the roles of CTSB/S and SIRT1 in the regulation of hepatic inflammation using primary parenchymal and non-parenchymal hepatic cell types and cell lines. In all cells analyzed, CTSB/S inhibition reduces nuclear p65-NF-κB and κB-dependent gene expression after LPS or TNF through enhanced SIRT1 expression. Accordingly, SIRT1 silencing was sufficient to enhance inflammatory gene expression. Importantly, in a dietary mouse model of non-alcoholic steatohepatitis, or in healthy and fibrotic mice after LPS challenge, cathepsins as well as NF-κB-dependent gene expression are activated. Consistent with the prominent role of cathepsin/SIRT1, cysteine cathepsin inhibition limits NF-κB-dependent hepatic inflammation through the regulation of SIRT1 in all in vivo settings, providing a novel anti-inflammatory therapeutic target in liver disease. Nature Publishing Group 2016-11 2016-11-10 /pmc/articles/PMC5260902/ /pubmed/27831566 http://dx.doi.org/10.1038/cddis.2016.368 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article de Mingo, Álvaro de Gregorio, Estefanía Moles, Anna Tarrats, Núria Tutusaus, Anna Colell, Anna Fernandez-Checa, Jose C Morales, Albert Marí, Montserrat Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation |
title | Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation |
title_full | Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation |
title_fullStr | Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation |
title_full_unstemmed | Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation |
title_short | Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation |
title_sort | cysteine cathepsins control hepatic nf-κb-dependent inflammation via sirtuin-1 regulation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260902/ https://www.ncbi.nlm.nih.gov/pubmed/27831566 http://dx.doi.org/10.1038/cddis.2016.368 |
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