AMPK Inhibition Blocks ROS-NFκB Signaling and Attenuates Endotoxemia-Induced Liver Injury

Abstract

BackgroundAMP-activated protein kinase (AMPK) is an important enzyme in regulation of cellular energy homeostasis. We have previously shown that AMPK activation by 5-aminoimidazole-4-carboxamide (AICAR) results in suppression of immune responses, indicating the pivotal role of AMPK in immune regulation. However, the cellular mechanism underpinning AMPK inhibition on immune response remains largely to be elucidated. The study aimed to investigate the effects of AMPK inhibition on reactive oxygen species (ROS)-nuclear factor κB (NFκB) signaling and endotoxemia-induced liver injury.Methodology/Principal FindingsRAW 264.7 cells were pretreated with AMPK activator or inhibitor, followed by LPS challenge. In addition, LPS was injected intraperitoneally into mice to induce systemic inflammation. The parameters of liver injury and immune responses were determined, and survival of mice was monitored respectively. LPS challenge in RAW 264.7 cells resulted in AMPK activation which was then inhibited by compound C treatment. Both AMPK activation by AICAR or inhibition by compound C diminished LPS-induced ROS generation, inhibited phosphorylation of IKK, IκB, and NFκB p65, and consequently, decreased TNF production of RAW 264.7 cells. AICAR or compound C treatment decreased ALT, AST, and TNF levels in serum, reduced CD68 expression and MPO activity in liver tissue of mice with endotoxemia. Moreover, AICAR or compound C treatment improved survival of endotoxemic mice.ConclusionsAICAR or compound C treatment attenuates LPS-induced ROS-NFκB signaling, immune responses and liver injury. Strategies to activate or inhibit AMPK signaling may provide alternatives to the current clinical approaches to inhibit immune responses of endotoxemia.

High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1

“…However, the relationship between the AMPK pathway and CD68 expression in the phenotype differentiation of monocytes/macrophages is rarely understood. A recent study of animal models of endotoxemia-induced liver injury demonstrated that AICAR, an AMPK activator, or Compound C, an AMPK inhibitor, could attenuate LPS-induced CD68 expression [42]. Our results suggested that HUA exposure can also activate the AMPK pathway and attenuate CD68 expression in cell differentiation, but Compound C can reverse this effect.…”

Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages

“…Confusingly, both AMPK activation and inhibition using synthetic agents have been shown to decrease LPS-induced liver injury (33). To clarify the results obtained by pharmacologically manipulating AMPK, genetic AMPK mutants were employed (34).…”

Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

“…A potential limitation of the present study is the heavy reliance on pharmacological agents to dissect signaling pathways [e.g., compound C, STO-609, and Zn(II)PPIX], leaving open the possibility for off-target effects. However, at the concentrations used, the compounds [STO-609 (5 mM), compound C (10 mM), and Zn(II)PPIX (5 mM)] are likely to have acted relatively specifically (Zhou et al, 2007;Nowis et al, 2008;Reihill et al, 2011;Guo et al, 2014).…”