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 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.
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Álvaro
Á
de Mingo
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Estefanía
E
de Gregorio
Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
Anna
A
Moles
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Núria
N
Tarrats
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Anna
0000-0002-1133-321X
A
Tutusaus
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Anna
A
Colell
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.|Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
Jose C
JC
Fernandez-Checa
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Albert
0000-0001-8702-2269
A
Morales
Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.
Montserrat
M
Marí
D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D002403:Cathepsins; D002401:Cathepsin B; C028217:cathepsin S; D056564:Sirtuin 1