Cysteine cathepsins control hepatic NF-[kappa]B-dependent inflammation via sirtuin-1 regulation

• Published in: Cell death & disease 2016-11, Vol.7 (11), p.e2464
• Main Authors: De Mingo, Álvaro, De Gregorio, Estefanía, Moles, Anna, Tarrats, Núria, Tutusaus, Anna, Colell, Anna, Fernandez-checa, Jose C, Morales, Albert, Marí, Montserrat
• Format: Article
• Language: English
• Subjects: Gene expression; Inflammation; Liver diseases; Metabolism; Proteins
• ISSN: 2041-4889
• DOI: 10.1038/cddis.2016.368

Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-B-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-B and B-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-B-dependent gene expression are activated. Consistent with the prominent role of cathepsin/SIRT1, cysteine cathepsin inhibition limits NF-B-dependent hepatic inflammation through the regulation of SIRT1 in all in vivo settings, providing a novel anti-inflammatory therapeutic target in liver disease.