Modulation of SIRT1-mediated signaling cascades in the liver contributes to the amelioration of nonalcoholic steatohepatitis in high fat fed middle-aged LDL receptor knockout mice by dihydromyricetin.

Dihydromyricetin (DMY) is the most abundant flavonoid in Ampelopsis grossedentata possessing many pharmacological activities. But less is known about its protective effect against nonalcoholic steatohepatitis (NASH) in the context of metabolic syndrome. The present study is aimed to evaluate the pharmacological effects of DMY on NASH induced by feeding a high fat diet to 12-mo-old male LDLr-/- mice for 12 weeks and its molecular mode of action. At the end of the experiment, the blood samples and liver tissues of mice were collected for analysis. The results showed that DMY treatment improved the steatosis, inflammation and fibrosis which are three main aspects of NASH and some of the metabolic basal characteristics. The underlying mechanisms include regulating key regulators of lipid metabolism, oxidative stress, inflammation and fibrosis. Notably, DMY treatment increased hepatic sirtuin 1 (SIRT1) activity and protein expression. DMY also enhanced deacetylation of liver kinase B1 (LKB1) and nuclear transcription factor kappa B (NF-kB). Furthermore, in cultured hepatocyte cells, the benefits of DMY on lipid accumulation, oxidative stress and inflammation as well as the above related genes were abrogated in hepatocytes transfected with SIRT1 siRNA. These results suggest that modulation of SIRT1-mediated signaling cascades contributes to the amelioration of NASH by DMY and DMY may serve as a potentialtherapeuticcandidate for human NASH.