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  • Interestingly we noticed that LPS exposure was

    2024-07-09

    Interestingly, we noticed that LPS exposure was associated with decreased phosphorylation of AMPK and increased phosphorylation of p70S6K1, suggesting that AMPK inactivation and the subsequent mTOR activation might be involved in the development of LPS-induced inflammation. On the other side, treatment with metformin restored AMPK-dependent mTOR inhibition, a potential endogenous anti-inflammatory mechanism contributing to the limitation of excessive inflammation. Therefore, LPS exposure might disturb AMPK-dependent suppression of mTOR, whereas treatment with metformin might restore this anti-inflammatory pathway. The important roles of mTOR in LPS-induced acute lung injury have been reported previously [41], but the underlying mechanisms remain unclear. A recent study found that mTOR is involved in the induction of components of proteasome, which degrades IκB and promotes the activation of NF-κB [18], which provide a mechanism explanation for the further understanding of the anti-inflammatory benefits of metformin. In addition to the AMPK-dependent mechansims, some AMPK-unrelated pathways are also involved in the anti-inflammatory actions of metformin. For example, metformin could inhibit mTOR signaling in the absence of AMPK, and the suppressed mTOR activation was dependent on the suppression of Rag GTPases and the upregulation of REDD1 by metformin [30,31]. Additionally, treatment with metformin suppressed the activity of phospholipase C [15], while phospholipase C has been recently found to play crucial roles in phosphorylation of STAT3, paricalcitol of inflammation-associated genes, infiltration of neutrophil and induction of microvascular leakage [16,42]. Therefore, suppression of phospholipase C might be anothe AMPK-independent anti-inflammatory mechanism of metformin.
    Conflicts of interest
    Acknowledgments This work was supported by the grants from the National Nature Science Foundation of China (No. 81370179, 81671953) and the grant from the Educational Commission of Hubei Province of China (No. Q20164307).
    Introduction The AMP-activated protein kinase (AMPK) regulates energy balance in the body (Mihaylova and Shaw, 2011; Carling et al., 2012; Hardie et al., 2012). Intracellular deficiency in ATP activates AMPK, which, in turn, promotes catabolic processes and inhibits anabolic processes by phosphorylation of multiple substrates, including acetyl-coenzyme A (CoA) carboxylase (ACC) and hydroxymethylglutaryl-CoA (HMG-CoA) reductase. The linkage of AMPK to metabolic processes renders AMPK a promising therapeutic target for obesity and type 2 diabetes (Zhang et al., 2009). AMPK is a heterotrimeric enzyme composed of a catalytic α subunit and two regulatory β and γ subunits. The γ subunit contains four cystathionine-β synthase (CBS) domains. Each CBS domain contains a binding site for an adenosine phosphate. Sites 1 and 3 bind AMP, ADP, or ATP in a concentration-dependent manner; site 4 constitutively binds to AMP; and site 2 is always empty. Phosphorylation of Thr172 of the α subunit and allosteric activation, both due to binding of AMP to the γ subunit, lead to a 1,000-fold increase in AMPK activity (Suter et al., 2006). AMP binding to AMPK also inhibits dephosphorylation of AMPK (Davies et al., 1995). Liver kinase B1 (LKB1) is the primary protein kinase responsible for the phosphorylation of this regulatory Thr172 residue (Hawley et al., 2003; Woods et al., 2003; Shaw et al., 2004). Increased intracellular AMP concentration drives assembly of the Axin-AMPK-LKB1 complex, thereby promoting AMPK phosphorylation by LKB1 (Zhang et al., 2013). Thus, in addition to the multiple CBS domains, Axin-mediated regulation contributes to the ultrasensitive system for the monitoring of intracellular AMP concentration. Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2, also known as CaMKKβ) has also been shown to phosphorylate Thr172 of the α subunit in a calcium-dependent manner (Hurley et al., 2005; Hawley et al., 2005). This pathway is known to function at least in neurons and T cells (Mihaylova and Shaw, 2011; Carling et al., 2012; Hardie et al., 2012).