Higher intestinal and circulatory lactate associated NOX2 activation leads to an ectopic fibrotic pathology following microcystin co-exposure in murine fatty liver disease.
Animals
Cell Line
Enzyme Inhibitors
/ toxicity
Fibrosis
/ enzymology
Intestinal Mucosa
/ drug effects
Intestines
/ drug effects
Lactic Acid
/ blood
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microcystins
/ toxicity
NADPH Oxidase 2
/ antagonists & inhibitors
Non-alcoholic Fatty Liver Disease
/ blood
Phosphorylation
Dysbiosis
Fibrosis
Lactate
MC-LR
NAFLD
NOX2
PP2A inhibitor
Peroxynitrite
Journal
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP
ISSN: 1532-0456
Titre abrégé: Comp Biochem Physiol C Toxicol Pharmacol
Pays: United States
ID NLM: 100959500
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
29
03
2020
revised:
14
06
2020
accepted:
03
07
2020
pubmed:
12
8
2020
medline:
4
3
2021
entrez:
12
8
2020
Statut:
ppublish
Résumé
Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.
Identifiants
pubmed: 32781293
pii: S1532-0456(20)30154-X
doi: 10.1016/j.cbpc.2020.108854
pmc: PMC7541568
mid: NIHMS1621945
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Microcystins
0
Lactic Acid
33X04XA5AT
microcystin
77238-39-2
Cybb protein, mouse
EC 1.6.3.-
NADPH Oxidase 2
EC 1.6.3.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
108854Subventions
Organisme : NIEHS NIH HHS
ID : P01 ES028942
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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