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.
Highlights
Autophagy is an intracellular pathway that targets and delivers cellular components such as organelles and protein aggregates to lysosomes for degradation
Autophagy dysfunction has been identified as a key factor in the pathogenesis of several diseases, ranging from neurodegenerative disorders, such as Parkinson disease to metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD) [1,2,3]
We focused on six flavonoid aglycons, found in fruits and leaves of Citrus family plants such as bergamot [15], which are the main compounds of Bergamot Polyphenol Fraction (BPF)®, previously characterized for its pro-autophagic effects in hepatocytes [7,38]
Summary
Autophagy is an intracellular pathway that targets and delivers cellular components such as organelles and protein aggregates to lysosomes for degradation. Autophagy dysfunction has been identified as a key factor in the pathogenesis of several diseases, ranging from neurodegenerative disorders, such as Parkinson disease to metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD) [1,2,3]. Natural polyphenols and in particular some flavonoids from Citrus family fruits such as bergamot have been shown to stimulate autophagy in liver cells [7,8] and prevent NAFLD in animal models and clinical studies [9,10,11]. The pro-autophagic activity of these compounds has been documented in several other cell and tissue types [12,13,14], and it is widely accepted that many flavonoids, alkaloids, and other polyphenols stimulate autophagy, besides their well-known antioxidant and anti-inflammatory effects [15,16,17].
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