Curcumol ameliorates alcoholic liver disease through regulation of SIRT1 signaling pathway.

Abstract

Curcumol has been demonstrated to ameliorate alcoholic liver disease (ALD) through inhibition of hepatocyte senescence. In view of the findings that curcumol was able to activate SIRT1 in hepatic stellate cells, the present study was designed to investigate whether curcumol could alleviate ALD through activating SIRT1 in hepatocytes. Mice were fed on Lieber-DeCarli liquid diet (containing 28 % of calories from ethanol) for 46 d to induce ALD, with curcumol administered intragastrically from the 17th to the 46th day. In vitro studies were conducted in hepatocytes exposed to ethanol (100 mmol/L) in the presence or absence of curcumol for 24 h. The results showed that curcumol was able to ameliorate ALD as indicated by pathological examination, decreased serum levels of ALT and AST and reduced hepatic lipid accumulation. Curcumol could alleviate ethanol-induced cell injury and lipid deposition in cultured hepatocytes. Further studies revealed that curcumol activated SIRT1 in the liver of alcohol fed mice and ethanol treated hepatocytes, accompanied by a marked upregulation of peroxisome proliferator activated receptor expression and AMP-activated protein kinase activation. The levels of adipose triglyceride lipase and hormone sensitive lipase expression and acetyl CoA carboxylase phosphorylation were consistently upregulated by curcumol treatment. Inhibition of SIRT1 with a specific inhibitor, EX527, neutralized curcumol's influence on SIRT1 signaling pathway, expression or activation of lipid metabolism related enzymes and lipid accumulation in hepatocytes. These results indicated that curcumol was able to ameliorate ALD through regulation of SIRT1 signaling pathway and subsequent promotion of lipolysis and inhibition of lipogenesis.