A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells

Abstract

Abstract Background WS070117 is a novel small molecule compound that significantly improves lipid metabolism disorders in high-fat-diet (HFD) induced hyperlipidemia in hamsters. Methods and Results We evaluated liver/body weight ratio, liver histology, serum and hepatic lipid content in HFD-fed hamsters treated with WS070117 for 8 weeks. Comparing with HFD fed hamsters, WS070117 (2 mg/kg per day and above) reduced serum triglyceride (TAG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and hepatic cholesterol and triglyceride contents. Oil Red O staining of liver tissue also showed that WS070117 improved lipid accumulation. We then carried out an experiment in the oleic acid (OLA)-induced steatosis model in HepG2 cell to investigate the lipid-lowering effect of WS070117. Oleic acid (0.25 mM) markedly induced lipid accumulation in HepG2 cells, but WS070117 (10 μM) inhibited cellular lipid accumulation. In OLA-treated HepG2 cells, WS070117 (above 1 μM) treatment reduced lipid contents which synthesized from [1-14C] labeled acetic acid. Because WS070117 is an analog of adenosine, we evaluated the effect of WS070117 on AMP-activated protein kinase (AMPK) signaling. The results showed that the activation of AMPK in OLA-induced steatosis in HepG2 cells was up-regulated by treatment with 0.1, 1 and 10 μM WS070117. The hepatic cellular AMPK phosphorylation is also up regulated by WS070117 (6 and 18 mg/kg) treatment in HFD fed hamsters. Conclusion These new findings identify WS070117 as a novel molecule that regulates lipid metabolism in the hyperlipidemia hamster model. In vitro and in vivo studies suggested that WS070117 may regulate lipid metabolism through stimulating the activation of AMPK and its downstream pathways.