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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Dietary flavonoids stimulate autophagy and prevent liver dysfunction, but the upstream signaling pathways triggered by these compounds are not well understood. Certain polyphenols bind directly to NRH-quinone oxidoreductase 2 (NQO2) and inhibit its activity. NQO2 is highly expressed in the liver, where it participates in quinone metabolism, but recent evidence indicates that it may also play a role in the regulation of oxidative stress and autophagy. Here, we addressed a potential role of NQO2 in autophagy induction by flavonoids. The pro-autophagic activity of seven flavonoid aglycons correlated perfectly with their ability to inhibit NQO2 activity, and flavones such as apigenin and luteolin showed the strongest activity in all assays. The silencing of NQO2 strongly reduced flavone-induced autophagic flux, although it increased basal LC3-II levels in HepG2 cells. Both flavones induced AMP kinase (AMPK) activation, while its reduction by AMPK beta (PRKAB1) silencing inhibited flavone-induced autophagy. Interestingly, the depletion of NQO2 levels by siRNA increased the basal AMPK phosphorylation but abrogated its further increase by apigenin. Thus, NQO2 contributes to the negative regulation of AMPK activity and autophagy, while its targeting by flavones releases pro-autophagic signals. These findings imply that NQO2 works as a flavone receptor mediating autophagy and may contribute to other hepatic effects of flavonoids.

Details

Title
Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells
Author
Janda, Elzbieta 1   VIAFID ORCID Logo  ; Martino, Concetta 2 ; Riillo, Concetta 2 ; Parafati, Maddalena 2   VIAFID ORCID Logo  ; Lascala, Antonella 2 ; Mollace, Vincenzo 1 ; Boutin, Jean A 3   VIAFID ORCID Logo 

 Department of Health Sciences, Campus Germaneto, Magna Graecia University, 88100 Catanzaro, Italy; [email protected] (C.M.); [email protected] (C.R.); [email protected] (M.P.); [email protected] (A.L.); [email protected] (V.M.); Interregional Research Center for Food Safety and Health, 88100 Catanzaro, Italy 
 Department of Health Sciences, Campus Germaneto, Magna Graecia University, 88100 Catanzaro, Italy; [email protected] (C.M.); [email protected] (C.R.); [email protected] (M.P.); [email protected] (A.L.); [email protected] (V.M.) 
 PHARMADEV (Pharmacochimie et Biologie Pour le Développement), Faculté de Pharmacie, Université Toulouse 3 Paul Sabatier, 31062 Toulouse, France; [email protected] 
First page
776
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
20763921
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2531379722
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.