Nuciferine protects against high-fat diet-induced hepatic steatosis and insulin resistance
Autophagy
Fatty liver
Lotus leaf
Lysosome
MiT/TFE
Ragulator
TFEB
mTORC1
Journal
Acta pharmaceutica Sinica. B
ISSN: 2211-3835
Titre abrégé: Acta Pharm Sin B
Pays: Netherlands
ID NLM: 101600560
Informations de publication
Date de publication:
Jun 2022
Jun 2022
Historique:
received:
24
09
2021
revised:
10
11
2021
accepted:
17
11
2021
entrez:
27
6
2022
pubmed:
28
6
2022
medline:
28
6
2022
Statut:
ppublish
Résumé
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy-lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.
Identifiants
pubmed: 35755273
doi: 10.1016/j.apsb.2021.12.012
pii: S2211-3835(21)00484-6
pmc: PMC9214335
doi:
Types de publication
Journal Article
Langues
eng
Pagination
2869-2886Informations de copyright
© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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