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 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.
Department of Endocrinology and Metabolism, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Bing
B
Zhou
Department of Endocrinology and Metabolism, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Dan-Li
DL
Zhou
Department of Endocrinology and Metabolism, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Xiao-Hong
XH
Wei
Department of Endocrinology and Metabolism, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Rong-Yu
RY
Zhong
Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Jie
J
Xu
Department of Endocrinology and Metabolism, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Liao
L
Sun
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D012503:Saponins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D012503:Saponins; D014315:Triterpenes; C052064:astragaloside A; D055372:AMP-Activated Protein Kinases