Acanthoic Acid Regulates Alcohol Exposure-induced Liver Lipid Deposition And Inflammation

Objective:Alcoholic liver disease has been the major cause of liver disease and death in America and worldwide. Alcoholic fatty liver caused by alcohol and its complications, which is observed as the first stage of ALD, has gradually become the leading cause of chronic liver disease. In this study, we established acute alcoholic fatty liver model by gavaging with alcohol three times after the last AA treatment. After that, we detected the serum related indicators, the pathological changes in liver tissues and the proteins to investigate the protective effect and the mechanism of AA in acute alcoholic fatty liver disease, and provide effective experimental data to the further development of AA.Methods:Mice were divided into six groups randomly, including normal group, ethanol group, AA (40 mg/kg) single group, AA (20 mg/kg) plus ethanol-treated group, AA (40 mg/kg) plus ethanol-treated group, and FFBJ group. Normal group and ethanol group received an isocalorical maltose solution, AA and FFBJ groups were given AA and FFBJ by gavaging every 12 h at the same time for 14 days. After the last treatment, the mice were fasting for 12 h, except normal and AA single group, other groups were given ethanol 3 times in 24 h.4 h after the last dosing, mice were anesthetized and blood samples were taken for serum biochemistry.Serum levels of aspartate a minotransferase (AST), alanine a minotransparferase (ALT) and Triglyceride(TG) were detected by kit. The pathological changes in liver tissues were evaluated by HE. The expressions of SREBP-1, CYP2E1, PPAR and AMPK-related proteins were detected by Western blot. The mRNA expressions of SREBP-1, Liver X receptor, IL-1β, IL-18, a-SMA, Collagen-1 and Timp-1 were measured by RT-PCR.Results:Compared with the normal group, ethanol administration significantly increased serum ALT, AST and TG levels in mice. While AA significantly decreased serum ALT, AST and TG levels caused by ethanol in a dose-dependent manner. The results of oil red showd that AA significantly decreased fat accumulation. Staining with hematoxy&lineosin(H&E) reversed pathological changes caused by ethanol, meanwhile AA significantly inhibited the positive expression of SREBP-1. AA significantly decreased the activities of Caspase-land IL-1(3 and increased the expression of IL-18 in liver tissue.AA significantly reversed the increase of SREBP-1 and CYP2E1 protein caused by ethanol. The expression of SREBP-1 mRNA showed the same result as Western Blot. Meanwhile the results of RT-PCR showed that in ethanol modle, AA significantly decreased the expressions of a-SMA, Collagen-1 and TIMP-1 mRNA; AA significantly increased the phosphorylation of AMPK, ACC and LKB-1 and enhanced the expression of SIRT1 of nuclear and total protein as well, and AA significantly decreased the inhibition of LXRa and LXRβ in mice. AA significantly ameliorated the decrease of PPARy and increase of PPARa caused by ethanol.Conclusions:AA effectively inhibited the levels of serum ALT, AST and TG and the activation of SREBP-1 and CYP2E1 and decreased the expressions of inflammation factors, so as to protect liver and inhibit the liver fibrosis. AA may through the activition of LXRs, PPAR and SIRT-AMPK to regulate the synthesis and metabolism of fatty acid.