Identification of adenine modulating AMPK activation in NIH/3T3 cells by proteomic approach

Young, Guang-Huar; Lin, Jiun‐Tsai; Cheng, Yingying; Huang, Chiung-Shing; Chao, Cheng-Yu; Nong, Jing-Yi; Chen, Po-Ku; Chen, Han-Min

doi:10.1016/j.jprot.2015.03.012

Cited by 15 publications

(17 citation statements)

References 43 publications

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“…AMPK is activated by both AMP and phosphorylation on Thr172 of α subunit by upstream kinases. Previous finding has suggested that adenine activates AMPK thereby inhibiting TNF-α signaling in HUVECs and glucose uptake in NIH-3T3 cells [ 32 33 ]. Hence we examined the effect of adenine on cellular AMP level and AMPK phosphorylation in RAW264.7 cells.…”

Section: Resultsmentioning

confidence: 99%

“…The AMP thereby activates AMPK to promote various physiological effects. Several reports suggest that adenine could be a novel and simplest AMPK activator [ 32 33 ]. However, in our experimental settings, we could not detect significant change in phosphorylation of AMPK at Thr172 and its downstream target ACC after adenine treatment ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Adenine attenuates lipopolysaccharide-induced inflammatory reactions

Silwal

Heo

Park

et al. 2018

Korean J Physiol Pharmacol

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A nucleobase adenine is a fundamental component of nucleic acids and adenine nucleotides. Various biological roles of adenine have been discovered. It is not produced from degradation of adenine nucleotides in mammals but produced mainly during polyamine synthesis by dividing cells. Anti-inflammatory roles of adenine have been supported in IgE-mediated allergic reactions, immunological functions of lymphocytes and dextran sodium sulfate-induced colitis. However adenine effects on Toll-like receptor 4 (TLR4)-mediated inflammation by lipopolysaccharide (LPS), a cell wall component of Gram negative bacteria, is not examined. Here we investigated anti-inflammatory roles of adenine in LPS-stimulated immune cells, including a macrophage cell line RAW264.7 and bone marrow derived mast cells (BMMCs) and peritoneal cells in mice. In RAW264.7 cells stimulated with LPS, adenine inhibited production of pro-inflammatory cytokines TNF-α and IL-6 and inflammatory lipid mediators, prostaglandin E2 and leukotriene B4. Adenine impeded signaling pathways eliciting production of these inflammatory mediators. It suppressed IκB phosphorylation, nuclear translocation of nuclear factor κB (NF-κB), phosphorylation of Akt and mitogen activated protein kinases (MAPKs) JNK and ERK. Although adenine raised cellular AMP which could activate AMP-dependent protein kinase (AMPK), the enzyme activity was not enhanced. In BMMCs, adenine inhibited the LPS-induced production of TNF-α, IL-6 and IL-13 and also hindered phosphorylation of NF-κB and Akt. In peritoneal cavity, adenine suppressed the LPS-induced production of TNF-α and IL-6 by peritoneal cells in mice. These results show that adenine attenuates the LPS-induced inflammatory reactions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adenine attenuates lipopolysaccharide-induced inflammatory reactions

Silwal

Heo

Park

et al. 2018

Korean J Physiol Pharmacol

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“…Adenine phosphoribosyltransferase (APRT) is an important enzyme in the salvage pathway, which functions as a catalyst in the reaction between adenine and phosphoribosyl pyrophosphate (PRPP) to produce AMP. Our previous findings suggest that adenine represents a novel AMPK activator, which could ameliorate LPS-induced inflammation in microglial BV2 cells and enhance glucose uptake in NIH-3T3 cells via the activation of AMPK [ 20 , 21 ]. However, the precise mechanism that underlies adenine-induced AMPK activation is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Activation of AMP-Activated Protein Kinase by Adenine Alleviates TNF-Alpha-Induced Inflammation in Human Umbilical Vein Endothelial Cells

Cheng¹,

Young²,

Lin³

et al. 2015

PLoS ONE

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The AMP-activated protein kinase (AMPK) signaling system plays a key role in cellular stress by repressing the inflammatory responses induced by the nuclear factor-kappa B (NF-κB) system. Previous studies suggest that the anti-inflammatory role of AMPK involves activation by adenine, but the mechanism that allows adenine to produce these effects has not yet been elucidated. In human umbilical vein endothelial cells (HUVECs), adenine was observed to induce the phosphorylation of AMPK in both a time- and dose-dependent manner as well as its downstream target acetyl Co-A carboxylase (ACC). Adenine also attenuated NF-κB targeting of gene expression in a dose-dependent manner and decreased monocyte adhesion to HUVECs following tumor necrosis factor (TNF-α) treatment. The short hairpin RNA (shRNA) against AMPK α1 in HUVECs attenuated the adenine-induced inhibition of NF-κB activation in response to TNF-α, thereby suggesting that the anti-inflammatory role of adenine is mediated by AMPK. Following the knockdown of adenosyl phosphoribosyl transferase (APRT) in HUVECs, adenine supplementation failed to induce the phosphorylation of AMPK and ACC. Similarly, the expression of a shRNA against APRT nullified the anti-inflammatory effects of adenine in HUVECs. These results suggested that the role of adenine as an AMPK activator is related to catabolism by APRT, which increases the cellular AMP levels to activate AMPK.

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“…Adenine can be converted to AMP by adenosyl phosphoribosyl transferase (APRTase) (7) and it subsequently binds and activates AMPK (6). Another AMPK activator, AICAR, binds to AMPK as ZMP.…”

Section: Adenine and Aicar Treatments Activate Ampk In Hfdpcsmentioning

confidence: 99%

“…AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis and was reported to inhibit mTORC1 (4) and activate NAD + -dependent enzymes (3,5) by increasing cellular NAD + levels to promote proliferation and prevent senescence. Recently, we reported that adenine can act as a true AMPK activator following conversion to AMP during purine salvage (6). Proteomic analysis revealed that adenine has a similar effect on NIH-3T3 cells to another AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside (AICAR).…”

Section: Introductionmentioning

confidence: 99%