1,3-dichloro-2-propanol induced hepatic lipid accumulation by inhibiting autophagy via AKT/mTOR/FOXO1 pathway in mice.
Animals
Autophagosomes
/ drug effects
Autophagy
/ drug effects
Blotting, Western
Forkhead Box Protein O1
/ metabolism
Hep G2 Cells
/ drug effects
Humans
Lipid Metabolism
/ drug effects
Liver
/ drug effects
Lysosomes
/ drug effects
Male
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ metabolism
alpha-Chlorohydrin
/ analogs & derivatives
1,3-Dichloro-2-propanol
AKT/mTOR/FOXO1 pathway
Autophagy
C57BL/6J mice
HepG2 cells
Lipid accumulation
Journal
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
ISSN: 1873-6351
Titre abrégé: Food Chem Toxicol
Pays: England
ID NLM: 8207483
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
23
06
2021
revised:
07
09
2021
accepted:
18
09
2021
pubmed:
25
9
2021
medline:
10
2
2022
entrez:
24
9
2021
Statut:
ppublish
Résumé
Our study investigated the effects of food contaminant 1,3-dichloro-2-propanol (1,3-DCP) on hepatic lipid metabolism and its mechanism. We found that triglyceride (TG), total cholesterol (TC) and the number of lipid droplets (LDs) were increased in the liver of C57BL/6 mice given intragastric administration of 1,3-DCP for 30 days. Meanwhile, 1,3-DCP inhibited autophagosomes and lysosomes formation, reflected by decreased LC3-II, LAMP1, LAMP2, CTSD, CTSB expression, increased p62 expression and decreased LC3 fluorescence. Subsequently, we detected the changes of hepatic lipid accumulation caused by 1,3-DCP using an autophagy inducer or inhibitor. In vivo, Hepatic lipid accumulation caused by 1,3-DCP was mitigated by the autophagy inducer Rapa. On the contrary, the autophagy inhibitor (chloroquine or 3-methyladenine) further exacerbated hepatic lipid accumulation caused by 1,3-DCP. 1,3-DCP reduced the number of autophagosomes encapsulated LDs, assessed by colocalization of LD and LC3. These data demonstrated that 1,3-DCP induced lipid accumulation by inhibiting autophagy. We further investigated the mechanism of 1,3-DCP-inhibited autophagy and found 1,3-DCP increased the ratios of p-AKT/AKT, p-mTOR/mTOR, p-FOXO1/FOXO1, decreased FOXO1 nuclear localization in vivo. These proteins may be involved in the regulation of 1,3-DCP-mediated autophagy. We detected the changes in autophagy marker protein LC3-II and lipid accumulation using an AKT inhibitor ARQ-092 or a mTOR inhibitor rapamycin in HepG2 cells. Compared with 1,3-DCP group, lipid accumulation was decreased, LC3-II and FOXO1 nuclear localization were increased, p-FOXO1 levels were decreased in HepG2 cells pretreated with ARQ-092 or rapamycin. Taken together, these data revealed that the effects of 1,3-DCP on lipid accumulation by inhibiting autophagy were dependent on AKT/mTOR/FOXO1 signaling pathway. Our study not only supplied the mechanism of 1,3-DCP toxicity, but also provided experimental basis for effective intervention measures of 1,3-DCP toxicity.
Identifiants
pubmed: 34560177
pii: S0278-6915(21)00611-6
doi: 10.1016/j.fct.2021.112578
pii:
doi:
Substances chimiques
Forkhead Box Protein O1
0
Foxo1 protein, mouse
0
1,3-dichloro-2-propanol
0F4P2VQC07
alpha-Chlorohydrin
96-24-2
mTOR protein, mouse
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112578Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.