Abstract
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 μg/mL) significantly attenuated this phenomenon. Notably, AS-IV (50–200 μg/mL) concentration-dependently enhanced the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and SREBP-1c, inhibited the accumulation and nuclear translocation of mature SREBP-1 and subsequently decreased the mRNA levels of lipogenic genes including acc1, fas and scd1. AS-IV treatment also concentration-dependently 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 μmol/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.
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This study was supported by a grant from the Natural Science Foundation of Guangdong Province, China (2016A030313286).
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Zhou, B., Zhou, Dl., Wei, Xh. et al. Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation. Acta Pharmacol Sin 38, 998–1008 (2017). https://doi.org/10.1038/aps.2016.175
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DOI: https://doi.org/10.1038/aps.2016.175
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