Desmethylbellidifolin protects against chronic alcoholic fatty liver disease by regulating Akt-mTORC1 pathway mediated autophagy / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To investigate the protective effect and potential mechanism of desmethylbellidifolin (DMB) in chronic alcoholic fatty liver disease. METHODS C57BL/6 mice were randomly divided into five groups. Control, meta?doxine and DMB group (high dose and low dose) mice were fed with Lieber-DeCarli liquid diet containing 5％alcohol for six weeks. Pair-fed group mice were fed with a liquid diet containing the same calories. After treatment, serum GOT, GPT, TG and hepatic T-CHO, TG, GSH, GSH-Px, SOD and CAT levels were measured. Ectopic liver lipid deposition was determined by oil red O and hematoxylin-eosin (HE) staining. Lipid metabolism and autophagy related genes expression were determined by real-time PCR and Western blotting. Electron microscope and laser scanning confocal microscope were used to detect autophagosome and autophagy flux. RESULTS DMB treatment markedly reduced serum TG, GOT and GPT levels in alcohol-induced mice, as well as hepatic levels of T-CHO, TG and MDA, while increased the GSH, GSH-Px, SOD and CAT levels in the liver. Oil red O and HE staining showed that the alcohol-induced lipid accumulation and hepatocyte morphology changes were significantly improved by DMB treatment. Mecha?nistically, the expression of stearoyl-CoA desaturase 1 and fatty acid synthase were significantly decreased, while lipoly?sis related hormone-sensitive lipase was elevated in mouse liver by DMB treatment. In addition, DMB could inhibit the phosphorylation of Akt and mTORC1, and activate autophagy process by inducing autophagy related genes expression, such as LC3, ATG5 and ATG7. Moreover, treatment with DMB notably increased the number of autolysosome and promote the autophagy flux, which may therefore induce the lipolysis and oxidation of lipids and prevent the alcohol-induced excessive lipid accumulation in the liver. CONCLUSION DMB exerts a protective role in alcoholic fatty liver dis?ease by regulating the Akt-mTORC1 pathway mediated autophagy activation.