Abstract
Background: Endoplasmic reticulum stress (ER stress) plays a critical role in the pathogenesis of liver fibrosis; thus, it can be a potential therapeutic target of fibrosis. However, the mechanism of ER stress regulation in fibrosis, particularly through sirtuin 1 (SIRT1), remains unclear. The objective of this study was to investigate the effect of SIRT1-mediated inhibition of ER stress in bile duct ligation (BDL)-induced liver fibrosis, and to explore the effect of salvianolic acid A (SalA) on BDL-induced liver fibrosis through SIRT1/heat shock factor 1 (HSF1) signaling.Materials and Methods: We explored the effects of SalA on liver fibrosis and ER stress in BDL-induced liver fibrosis in rats and the human hepatic stellate cell line LX2 cells. The LX2 cells were treated with 20 ng of platelet-derived growth factor-BB homodimer (PDGF-BB) for 24 h, and then incubated in the absence or presence of SalA (25 μM) for 24 h.Results: In vivo, SalA treatment alleviated BDL-induced liver injury and ER stress. Importantly, SalA treatment increased HSF1 expression and activity using a SIRT1-dependent mechanism. In LX2 cells, PDGF-BB induced ER stress and fibrosis were blocked by HSF1 overexpression. Furthermore, SIRT1 siRNA abrogated the SalA-mediated promotion of HSF1 deacetylation and expression, suggesting that SalA-mediated protection occurs by SIRT1 targeting HSF1 for deacetylation.Conclusion: This is the first study to identify the SIRT1/HSF1 pathway as a key therapeutic target for controlling BDL-induced liver fibrosis and to show that SalA confers protection against BDL- and PDGF-BB-induced hepatic fibrosis and ER stress through SIRT1-mediated HSF1 deacetylation.
Highlights
Liver fibrosis is a leading cause of liver health problems worldwide because of viral infection, alcoholism, chemical toxicity or metabolic and biliary disorders (Hernandez-Gea and Friedman, 2011; Sant’Anna et al, 2011)
Bilirubin levels in mice treated with salvianolic acid A (SalA) were not different from those in vehicle-treated animals after bile duct ligation (BDL), indicating that the degree of cholestasis was similar in all experimental groups (Figure 1C)
We found that the protein levels of P-protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)/PERK, P-IRE1α/inositol-requiring protein 1α (IRE-1α), activating transcription factor 6 (ATF6) and glucose regulated protein 78 (GRP78) were remarkably increased in the BDL group, whereas SalA treatment prevented the increase in levels of ER stress proteins
Summary
Liver fibrosis is a leading cause of liver health problems worldwide because of viral infection, alcoholism, chemical toxicity or metabolic and biliary disorders (Hernandez-Gea and Friedman, 2011; Sant’Anna et al, 2011). Studies have suggested that endoplasmic reticulum (ER) and oxidative stress may play a critical role in the pathogenesis of liver cirrhosis (Wu et al, 2014). Over the past two decades, ER stress has emerged as an important mechanism involved in the pathogenesis of human diseases, such as diabetes, obesity, neurodegenerative disorders and cancer (Minamino and Kitakaze, 2010). Understanding the molecular mechanisms that regulate ER stress may support the development of further therapeutic strategies for preventing and treating liver fibrosis. Endoplasmic reticulum stress (ER stress) plays a critical role in the pathogenesis of liver fibrosis; it can be a potential therapeutic target of fibrosis. The objective of this study was to investigate the effect of SIRT1-mediated inhibition of ER stress in bile duct ligation (BDL)-induced liver fibrosis, and to explore the effect of salvianolic acid A (SalA) on BDL-induced liver fibrosis through SIRT1/heat shock factor 1 (HSF1) signaling
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