Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 05 2023
04 05 2023
Historique:
received:
16
06
2020
accepted:
18
04
2023
medline:
8
5
2023
pubmed:
5
5
2023
entrez:
4
5
2023
Statut:
epublish
Résumé
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.
Identifiants
pubmed: 37142604
doi: 10.1038/s41467-023-38165-6
pii: 10.1038/s41467-023-38165-6
pmc: PMC10160018
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2573Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA026914
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG060456
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG063373
Pays : United States
Organisme : NIBIB NIH HHS
ID : T32 EB006359
Pays : United States
Informations de copyright
© 2023. The Author(s).
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