Mitochondrial Energy-Regulating Effect of Atractyloside Inhibits Hepatocellular Steatosis Through the Activation of Autophagy.
atractyloside
autophagy
hepatocellular steatosis
mitochondrial adaptation
triglyceride
Journal
Frontiers in pharmacology
ISSN: 1663-9812
Titre abrégé: Front Pharmacol
Pays: Switzerland
ID NLM: 101548923
Informations de publication
Date de publication:
2020
2020
Historique:
received:
24
06
2020
accepted:
11
09
2020
entrez:
26
10
2020
pubmed:
27
10
2020
medline:
27
10
2020
Statut:
epublish
Résumé
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). 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. 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. 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.
Sections du résumé
BACKGROUND AND AIM
OBJECTIVE
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 33101031
doi: 10.3389/fphar.2020.575695
pmc: PMC7556285
doi:
Types de publication
Journal Article
Langues
eng
Pagination
575695Informations de copyright
Copyright © 2020 Zhang, Li, Sun, Zhang, Zhang, Zhang and Zeng.
Références
Biomed Res Int. 2013;2013:403491
pubmed: 24371823
Chem Biol Interact. 2007 Jan 30;165(2):106-16
pubmed: 17188672
Nat Cell Biol. 2011 Feb;13(2):132-41
pubmed: 21258367
Pharmacol Ther. 1995;67(1):101-54
pubmed: 7494860
J Anim Physiol Anim Nutr (Berl). 2018 Aug;102(4):939-946
pubmed: 29604137
Structure. 2010 Jan 13;18(1):39-46
pubmed: 20152151
J Appl Toxicol. 2012 Jun;32(6):402-8
pubmed: 21598287
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
PLoS One. 2013 Apr 09;8(4):e61499
pubmed: 23585904
Ther Drug Monit. 2000 Dec;22(6):641-9
pubmed: 11128230
Cell Metab. 2018 Jan 9;27(1):22-41
pubmed: 28867301
BMC Med. 2017 Feb 28;15(1):45
pubmed: 28241825
Nat Commun. 2017 Feb 16;8:14477
pubmed: 28205519
Nature. 2009 Apr 30;458(7242):1131-5
pubmed: 19339967
J R Soc Interface. 2018 Jan;15(138):
pubmed: 29343628
Cell Biol Int. 2018 Apr;42(4):384-392
pubmed: 29205673
Biochem J. 2006 Nov 1;399(3):405-14
pubmed: 16831128
Cells. 2019 Jul 30;8(8):
pubmed: 31366145
Cell. 2014 Jun 5;157(6):1339-1352
pubmed: 24906151
Nutr Diabetes. 2018 Sep 24;8(1):53
pubmed: 30250193
Am J Physiol Endocrinol Metab. 2016 Oct 1;311(4):E730-E740
pubmed: 27577854
Bioorg Med Chem Lett. 2012 Apr 15;22(8):2973-5
pubmed: 22425567
Drug Metab Rev. 2012 Feb;44(1):34-87
pubmed: 21892896
Nat Metab. 2019 Jan;1(1):86-97
pubmed: 31528845
Curr Opin Lipidol. 2018 Jun;29(3):203-211
pubmed: 29601311
Cell Cycle. 2015;14(11):1631-42
pubmed: 25927598