The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders

Antonioli, Luca; Colucci, Rocchina; Pellegrini, Carolina; Giustarini, Giulio; Sacco, Deborah; Tirotta, Erika; Caputi, Valentina; Marsilio, Ilaria; Giron, Maria Cecilia; Németh, Zoltán; Blandizzi, Corrado; Fornai, Matteo

doi:10.1517/14728222.2016.1086752

Cited by 47 publications

(33 citation statements)

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“…Furthermore, both AICAR and AMP activate the 5′ adenosine monophosphate-activated protein kinase (AMPK) [ 78 ]. AMPK activation is protective towards endothelial cell function and vascular homeostasis, by ensuring physiological NO synthesis, maintaining mitochondrial structure and function, and preventing oxidative stress and apoptosis [ 79 ]. Moreover, a role for AMPK in inhibiting vascular smooth muscle cell proliferation, a key proatherosclerotic event both in autoimmune rheumatic diseases and in the general population, has been proposed [ 80 , 81 ].…”

Section: Methotrexate Pharmacologymentioning

confidence: 99%

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

Mangoni

Zinellu

Sotgia

et al. 2017

Mediators of Inflammation

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There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.

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Section: Methotrexate Pharmacologymentioning

confidence: 99%

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

Mangoni

Zinellu

Sotgia

et al. 2017

Mediators of Inflammation

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“…AMPK is a heterotrimer composed of α, β, and γ subunits ( 2 ). The α subunit is the catalytic subunit, the phosphorylation of the Thr 172 in the α subunit is a hallmark of AMPK activation ( 3 ). The regulatory γ subunit binds AMP/ADP under falling energy status and facilitates the phosphorylation of AMPKα and the activation of AMPK ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the anti-inflammatory benefits of the AMPK activators have been observed in animal models with colitis, hepatitis, and myocarditis ( 10 – 12 ). Therefore, AMPK is generally regarded as a negative regulator of inflammation ( 3 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-Induced Dephosphorylation of AMPK-Activated Protein Kinase Potentiates Inflammatory Injury via Repression of ULK1-Dependent Autophagy

Fan

et al. 2018

Front. Immunol.

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AMP-activated protein kinase (AMPK) is a crucial metabolic regulator with profound modulatory activities on inflammation. Although the anti-inflammatory benefits of AMPK activators were well documented in experimental studies, the pathological significance of endogenous AMPK in inflammatory disorders largely remains unknown. This study investigated the phosphorylation status of endogenous AMPK and the potential roles of AMPK in mice with lipopolysaccharide (LPS)-induced lethal inflammation. The results indicated that LPS dose-dependently decreased the phosphorylation level of AMPK and its target protein acetyl-CoA carboxylase (ACC). Reactivation of AMPK with the AMPK activator A-769662 suppressed LPS-induced elevation of interleukin 6, alleviated histological abnormalities in lung and improved the survival of LPS-challenged mice. Treatment with A-769662 restored LPS-induced suppression of autophagy, inhibition of autophagy by 3-MA reversed the beneficial effects of A-769662. Treatment with A-769662 suppressed LPS-induced activation of mammalian target of rapamycin (mTOR), co-administration of mTOR activator abolished the beneficial effects of A-769662, and the suppressive effects of A-769662 on uncoordinated-51-like kinase 1 (ULK1) phosphorylation. Inhibition of ULK1 removed the beneficial effects of A-769662. These data indicated that LPS-induced dephosphorylation of AMPK could result in weakened inhibition of mTOR and repression of ULK1-dependent autophagy, which might potentiate the development of LPS-induced inflammatory injury. These data suggest that pharmacological restoration of AMPK activation might be a beneficial approach for the intervention of inflammatory disorders.

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“…In addition to the regulation of cellular metabolism, published evidence supports that adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) exerts anti-inflammatory and immunosuppressive effects. AMPK signaling was found to be involved in controlling immune-related diseases such as autoimmune encephalomyelitis, arthritis, and inflammatory bowel disease [ 27 , 28 ]. AMPK is highly expressed in several immune cell types, including macrophages, lymphocytes and dendritic cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…AMPK signaling was found to be involved in controlling immune-related diseases such as autoimmune encephalomyelitis, arthritis, and inflammatory bowel disease [ 27 , 28 ]. AMPK is highly expressed in several immune cell types, including macrophages, lymphocytes and dendritic cells [ 28 ]. After AMPK activation, by agents such as metformin and the AMP analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), T-cell mediated immune responses can be suppressed, as shown by inhibition of T-cell differentiation and reduction of cytokines and chemokines [ 29 – 31 ].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Berberine on Concanavalin A-Induced Autoimmune Hepatitis (AIH) in Mice and the Adenosine 5’-Monophosphate (AMP)-Activated Protein Kinase (AMPK) Pathway

Wang

Zhou

et al. 2017

Med Sci Monit

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BackgroundBerberine, a herbal extract, has been reported to protect against inflammatory disorders. The adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway can be activated by berberine and inhibited by the synthetic, reversible AMP-competitive inhibitor, Compound C. The aim of this study was to investigate the effects of berberine on concanavalin A (Con A)-induced autoimmune hepatitis (AIH) in mice via the AMPK pathway.Material/MethodsBALB/c mice were treated with berberine, with or without Compound C, followed by treatment with Con A. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Liver tissue histology was performed to evaluate hepatic injury and AIH. Cytokine levels in serum and hepatic tissue were measured by enzyme-linked immunoassay (ELISA) and used quantitative polymerase chain reaction (qPCR). Levels of phosphorylated acetyl coenzyme-A carboxylase (ACC), representing AMPK activation, were detected by Western blotting.ResultsSerum ALT and AST levels were significantly reduced by berberine (100 and 200 mg/kg/day) in mice with Con A-induced hepatitis. Berberine also reduced Con A-induced hepatocyte swelling, cell death, and infiltration of leukocytes. Serum levels of tumor necrosis factor (TNF)-alpha, interferon (IF)-gamma, interleukin (IL)-2, and IL-1beta were reduced by berberine pre-treatment; levels of serum IL-10, an anti-inflammatory cytokine, was elevated. These protective effects of berberine on Con-A-induced AIH were reversed by treatment with Compound C.ConclusionsIn a murine model of Con A-induced AIH, berberine treatment reduced hepatic injury via activation of the AMPK pathway. Further studies are recommended to determine the potential therapeutic role for berberine in AIH.

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The AMPK enzyme-complex: from the regulation of cellular energy homeostasis to a possible new molecular target in the management of chronic inflammatory disorders

Cited by 47 publications

References 100 publications

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

Lipopolysaccharide-Induced Dephosphorylation of AMPK-Activated Protein Kinase Potentiates Inflammatory Injury via Repression of ULK1-Dependent Autophagy

The Effects of Berberine on Concanavalin A-Induced Autoimmune Hepatitis (AIH) in Mice and the Adenosine 5’-Monophosphate (AMP)-Activated Protein Kinase (AMPK) Pathway

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