Sirtuin 1 activation alleviates primary biliary cholangitis via the blocking of the NF-kappa B signaling pathway

摘要

This report sought to establish the mechanistic role of sirtuin-1 (Sirt1), a NAD(+)-dependent deacetylase in the modulation of primary biliary cholangitis (PBC) pathogenesis. 64 PBC patients (diagnosed based on practice guidelines for American Association for the Study of Liver Diseases) and 60 healthy controls were included in this study. Clinically, the mRNA expression level of Sirt1 in macrophages differentiated from peripheral blood mononuclear cells (PBMCs) of PBC subjects substantially decreased when compared with the healthy controls but not in other Sirt family genes (Sirt2-7). Consistent with clinical results, a PBC murine model showed that levels of Sirt1 significantly decreased in the liver and Kupffer cells of mice treated with polyinosinic/polycytidylic acid (poly I:C) for 16 weeks. A TAK1 inhibitor (NG25) prevented the poly I:C-induced Sirt1 protein level decreasing in Kupffer cells but not MAPK inhibitor. Sirt1 activators resveratrol (RSV) and SRT1720 (SRT) ameliorated poly I:C-induced hepatic injury observed via histopathologic analysis and decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the PBC murine model. Furthermore, Sirt1 activators significantly reduced pro-inflammatory cytokines levels such as interleukin-1 beta (IL-1 beta), IL-6, interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in serum in poly I:C-induced mice. In addition, Sirt1 activators significantly inhibited the phosphorylated and acetylated levels of the RelA/p65 subunit of the nuclear transcription factor (NF-kappa B) but not the interferon regulatory factor (IRF) 3 in poly I:C-injured mice livers. Significantly, RSV improved the interaction between Sirt1 and p65, which may contribute to the decreased activity of NF-kappa B. In summary, the Sirt1 signaling pathway plays an essential role in the development of PBC and this may represent a novel approach and target for the treatment of PBC.