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

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.

• Authors: Bing Zhou, Dan-Li Zhou, Xiao-Hong Wei, Rong-Yu Zhong, Jie Xu, Liao Sun
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 38 Issue 7 Pg. 998-1008 (Jul 2017) ISSN: 1745-7254 [Electronic] United States
• PMID: 28344322 (Publication Type: Journal Article)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Hspa5 protein, mouse
• Saponins
• Triterpenes
• astragaloside A
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Hep G2 Cells
• Hepatocytes (drug effects, enzymology, metabolism)
• Humans
• Lipid Metabolism (drug effects)
• Mice
• Mice, Inbred C57BL
• Molecular Conformation
• Saponins (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship
• Triterpenes (administration & dosage, chemistry, pharmacology)