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  • AMP activated protein kinase AMPK is composed

    2023-01-04

    AMP-activated protein kinase (AMPK) is composed of α-, β-, and γ-subunits [17,18]. Phosphorylation of α-subunit at Thr-172 residue is essential for AMPK activation [17,18]. The serine/threonine kinase coordinates metabolic pathways in response to energy supply and demand [17,18]. Studies have shown that activated AMPK can promote cell survival under stress conditions [19]. AMPK could efficiently inhibit oxidative stress via preserving nicotinamide ion channels dinucleotide phosphate (NADPH) [20] and activating Nrf2 signaling [[21], [22], [23]]. Recent studies have developed PF-06409577 as a selective and potent AMPK activator [24]. Unlike other AMPK activators, PF-06409577 directly binds to AMPK, leading to fast and potent AMPK activation [24]. In the current study, we show that PF-06409577 inhibits UVR-induced oxidative stress and RPE cell death by activating AMPK signaling.
    Materials and methods
    Results
    Discussion AMPK coordinates metabolic pathways in response to energy supply and demand [41]. AMPK can promote cell survival under different stress conditions [19]. Here, PF-06409577 activated AMPK signaling in ARPE-19 cells and the primary murine RPE cells. The AMPK activator significantly inhibited UVR-induced viability reduction, cell death and apoptosis in RPE cells. PF-06409577 can induce significant AMPK activation at only nM concentrations, which is significantly more efficient than known AMPK activators (i.e. AICAR, A769662 and metformin). This could possibly be due to the fact that PF-06409577 directly binds to AMPK, causing early and potent AMPK activation [24]. Existing studies have shown that activated AMPK can inhibit oxidative stress under stress conditions. AMPK regulates NADPH homeostasis [20]. Activated AMPK inactivates ACC to prevent NADPH depletion [20]. Furthermore, AMPK activation can promote fatty-acid oxidation to increase NADPH synthesis [20]. Recent studies have proposed another mechanism of AMPK-mediated anti-oxidative activity: by regulating Nrf2 signaling activation. Joo et al., demonstrated that AMPK can directly phosphorylate Nrf2 (at Serine 550) to promote its nuclear translocation [22]. Zimmermann et al., have proposed a signaling crosstalk between AMPK and Nrf2 signalings [21]. Similarly, a very recent study has shown that compound 991, another AMPK activator, induces AMPK-dependent Nrf2 signaling activation [23]. In line with these findings, we show that PF-06409577 increased NADPH activity (NADPH/NADP+) and expression levels of Nrf2-dependent genes in RPE cells. Significantly, the AMPK activator largely inhibited UVR-induced ROS production, lipid peroxidation and DNA damage in RPE cells. Thus, oxidative stress inhibition could be the primary reason of PF-06409577-mediated RPE cytoprotection against UVR.
    Fundings This work is supported by the Fund of Huaian First People's Hospital.
    Conflicts of interest
    Introduction Increases in human over-nutrition have expanded the incidence of metabolic disorders and raised the risk of cardiovascular events, causing a significant societal burden. The etiology of the set of conditions that make up this cardio-metabolic syndrome is complex and involves alterations in systemic lipid and glucose metabolism, in addition to cardiovascular and renal diseases. The liver plays a key role in the syndrome as an integrator of the hormonal and metabolic signals that regulate lipid and glucose synthesis and their transit to peripheral tissues (Reccia et al., 2017; Tilg et al., 2017). These hepatic actions are dysregulated in the cardio-metabolic syndrome, with excessive ion channels de novo production, storage, and trafficking of fatty acids and cholesterol, increasing cardiovascular risk factors and driving non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and increasing the likelihood of hepatocellular carcinoma (HCC) (Bril and Cusi, 2017). Pharmaceutical therapies that halt or reverse the hepatic abnormalities associated with this altered metabolic state are needed to lessen the increasing burden of resulting diseases on societies around the world.