Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation

Although the pathogenesis of non-alcoholic fatty liver disease （NAFLD） is not completely understood, the increased influx of free fatty acids （FFAs） into the liver and the FFA-induced hepatic endoplasmic reticulum （ER） stress are two crucial pathogenic processes in the initiation and development of NAFLD. In this study we investigated the effects of astragaloside IV （AS-IV）, a bioactive compound purified from Astragali Radix, on FFA-induced lipid accumulation in hepatocytes and elucidated the underlying mechanisms. Human HepG2 cells and primary murine hepatocytes were exposed to FFAs （1 mmol/L, oleate/palmitate, 2：1 ratio） with or without AS-IV for 24 h. Exposure to FFAs induced marked lipid accumulation in hepatocytes, whereas co-treatment with AS-IV （100 pg/mL） significantly attenuated this phenomenon. Notably, AS-IV （50-200 pg/mL） concentration-dependently enhanced the phosphorylation of AMPK, acetyl-CoA carboxylase （ACC） and SREBP-lc, inhibited the accumulation and nuclear translocation of mature SREBP-1 and subsequently decreased the mRNA levels of lipogenic genes including accl, fas and scdl. AS-IV treatment also concentrationdependently attenuated FFA-induced hepatic ER stress evidenced by the reduction of the key markers, GRP78, CHOP and p-PERK. Pretreated the cells with the AMPK inhibitor compound C （20 pmol/L） greatly diminished these beneficial effects of AS-IV. Our results demonstrate that AS-IV attenuates FFA-induced ER stress and lipid accumulation in an AMPK-dependent manner in hepatocytes, which supports its use as promising therapeutics for hepatic steatosis.