Important Role of Sirt1 In the Survival and Activation of Hepatic Stellate Cells During Liver Injury

Background and Aims: Hepatic stellate cells (HSC) represent 15% of the total resident cells in normal liver. Following liver injury, HSC transform into proliferating profibrogenic myofibroblasts. SIRT1, a NAD-dependent histone deacetylase, the activation of which is correlated with prosurviving phenotype in many cell lines, is normally expressed in liver. Resveratrol, a polyphenol found in wines was reported to be an activator of SIRT1. We investigated the role of SIRT1 activation in HSC during liver injury as a possible therapeutic target for liver fibrosis. Methods: We evaluated the expression of SIRT1 in freshly isolated human HSC and its role in response to stress conditions. We also tested the in vivo effects of SIRT1 modulation in mice exposed to carbon tetrachloride-induced liver injury. Results: We found that SIRT1 is normally expressed in human and mouse HSCs; its activation reduces proapoptotic effects of hydrogen peroxide in HSC. Treating the cells with the SIRT1 inhibitor EX-527 resulted in increased apoptosis and reduced activation. In the in vivo model EX-527 treated animals showed decreased level of HSC activation as well as reduced collagen deposition. Conclusions: SIRT1 inhibition in HSC increases stress-related apoptosis and decreases cell activation in vitro and decreases the number of activated and proliferating HSC in the animal model of liver injury. The inhibition of SIRT1 could therefore prevent the fibrogenic alteration of the parenchyma during liver injury.