Janda Elzbieta, Martino Concetta, Riillo Concetta, Parafati Maddalena, Lascala Antonella, Mollace Vincenzo, Boutin Jean A
Department of Health Sciences, Campus Germaneto, Magna Graecia University, 88100 Catanzaro, Italy.
Interregional Research Center for Food Safety and Health, 88100 Catanzaro, Italy.
Antioxidants (Basel). 2021 May 13;10(5):776. doi: 10.3390/antiox10050776.
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.
膳食类黄酮可刺激自噬并预防肝功能障碍，但其引发的上游信号通路尚未完全明确。某些多酚可直接与NRH-醌氧化还原酶2（NQO2）结合并抑制其活性。NQO2在肝脏中高表达，参与醌代谢，但最近的证据表明它可能也在氧化应激和自噬的调节中发挥作用。在此，我们探讨了NQO2在类黄酮诱导自噬中的潜在作用。七种类黄酮苷元的促自噬活性与其抑制NQO2活性的能力完美相关，芹菜素和木犀草素等黄酮在所有实验中表现出最强的活性。NQO2的沉默显著降低了黄酮诱导的自噬通量，尽管它增加了HepG2细胞中的基础LC3-II水平。两种黄酮均诱导AMP激酶（AMPK）激活，而通过AMPKβ（PRKAB1）沉默降低其水平则抑制了黄酮诱导的自噬。有趣的是，通过siRNA降低NQO2水平增加了基础AMPK磷酸化，但消除了芹菜素对其的进一步增加作用。因此，NQO2有助于对AMPK活性和自噬的负调节，而黄酮对其的靶向作用释放出促自噬信号。这些发现表明，NQO2作为介导自噬的黄酮受体发挥作用，可能对类黄酮的其他肝脏效应也有贡献。
