Mitochondrial Energy-Regulating Effect of Atractyloside Inhibits Hepatocellular Steatosis Through the Activation of Autophagy

Zhang，Pengfei1,2,3; Li，Lijun4; Sun，Huimin1; Zhang，Yipeng5; Zhang，Guoliang6; Zhang，Tianyu2,3; Zeng，Changchun1

2020-09-30

10.3389/fphar.2020.575695

Frontiers in Pharmacology   影响因子和分区

1663-9812

1663-9812

Background and Aim: Atractyloside (ATR), a mitochondrial uncoupler, is known for its specific inhibition of mitochondrial oxidative phosphorylation. Previous studies have reported that moderate mitochondrial uncoupling effect is beneficial to increase the decomposition and clearance of hepatic lipid, prevent the occurrence of fatty liver diseases. Moreover, the beneficial effects of mitochondrial uncouplers on type 2 diabetes and metabolic syndromes have been consistently observed. The present study investigated the effect of ATR on steatosis level of HepG2 cells treated with free fatty acid (FFA). Methods: Intracellular triglyceride level and Oil Red O staining were assessed, the mitochondrial adaptation and ADP/ATP ratio were analyzed, the protein level of AMPK, mTOR and LC3B, autophagic flux, and the co-localization of LC3B with lipid droplets was performed. Results: ATR treatment inhibited the activity of mitochondrial respiratory chain complexes I and IV, decreased the mitochondrial membrane potential, and increased the ADP/ATP ratio in the FFA-treated cells. Furthermore, ATR increased the gene expression and protein level of LC3B and promoted the autophagic flux processing from early autophagosome to late autolysosome by increasing the protein level of AMPKα and decreasing the protein level of mTOR. An increased number of autophagosomes (LC3B) was also observed in the lipid droplets. ATR treatment accelerated lipid degradation in the FFA-treated cells, and the lowest lipid content was observed in the cell group with 7.5 μM ATR. Conclusion: Low concentrations (2.5, 5, and 7.5 μM) of ATR treatment could activate autophagy to accelerate the degradation of TGs in steatosis HepG2 cells; the mechanism may be related to the activation of the AMPK/mTOR pathway induced by the increased ADP/ATP ratio. In addition, the ideal concentration of ATR for improving steatotic HepG2 cells was 7.5 μM.

atractyloside autophagy hepatocellular steatosis mitochondrial adaptation triglyceride

SCI

英语

其他

National Natural Science Foundation of China[81660755] ; Science and Technology Project of Shenzhen of China[JCYJ20170307160524377][JCYJ20190808162605484] ; Science and Technology Project of Longhua District of Shenzen[2017083]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000577542500001

FRONTIERS MEDIA SA

2-s2.0-85092727116

Scopus

1.Department of Medical Laboratory,Shenzhen Longhua District Central Hospital,Shenzhen,China
2.State Key Laboratory of Respiratory Disease,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,China
3.University of Chinese Academy of Sciences,Beijing,China
4.Department of Quality Control,Shenzhen Longhua District Central Hospital,Shenzhen,China
5.Clinical Laboratory,Shenzhen Longhua District Central Hospital,Shenzhen,China
6.National Clinical Research Center for Infectious Diseases,Guangdong Key Laboratory for Emerging Infectious Diseases,Shenzhen Third People’s Hospital,Southern University of Science and Technology,Shenzhen,China

Zhang，Pengfei,Li，Lijun,Sun，Huimin,et al. Mitochondrial Energy-Regulating Effect of Atractyloside Inhibits Hepatocellular Steatosis Through the Activation of Autophagy[J]. Frontiers in Pharmacology,2020,11.

Zhang，Pengfei.,Li，Lijun.,Sun，Huimin.,Zhang，Yipeng.,Zhang，Guoliang.,...&Zeng，Changchun.(2020).Mitochondrial Energy-Regulating Effect of Atractyloside Inhibits Hepatocellular Steatosis Through the Activation of Autophagy.Frontiers in Pharmacology,11.

Zhang，Pengfei,et al."Mitochondrial Energy-Regulating Effect of Atractyloside Inhibits Hepatocellular Steatosis Through the Activation of Autophagy".Frontiers in Pharmacology 11(2020).