Carnosic acid alleviates chronic alcoholic liver injury by regulating the SIRT1/ChREBP and SIRT1/p66shc pathways in rats

Scope: Carnosic acid (CA), which is extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the effects of CA on chronic alcoholic liver injury and to elucidate the related mechanisms. Methods and results: An in vivo ratmodel was established by feeding rats a liquid diet containing ethanol, and an in vitromodel was created by treating HepG2 cells with 100 mM ethanol for 48 h. In the ratmodel of alcohol-induced liver injury, CA significantly decreased serum aminotransferase, triglyceride and total cholesterol levels. Additionally, CA inhibited oxidative stress, inflammation, and cell death. Interestingly, CA activated SIRT1, which was associated with the downregulation of lipoprotein carbohydrate response element-binding protein (ChREBP) and growth factor adapter protein (p66shc). In HepG2 cells, ethanol-induced cell injury was associated with decreased SIRT1 and increased ChREBP and p66shc protein expression. These changes were reversed by CA but enhanced by a specific SIRT1 inhibitor, EX527. Moreover, the effects of CA on SIRT1, ChREBP, and p66shc were abolished by SIRT1 siRNA or EX527, indicating that CA decreased ChREBP and p66shc expression via SIRT1 activation. Conclusion: CA exerted protective effects against alcoholic liver injury by activating the SIRT1/ChREBP and SIRT1/p66shc pathways, which are related to the anti-steatosis, antioxidant, and anti-apoptosis effects.