AICAR inhibits PPARγ during monocyte differentiation to attenuate inflammatory responses to atherogenic lipids

Namgaladze, Dmitry; Kemmerer, Marina; Knethen, Andreas von; Brüne, Bernhard

doi:10.1093/cvr/cvt073

Cited by 26 publications

(19 citation statements)

References 42 publications

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“…2E and data not shown), suggests that other mechanisms of translational attenuation may operate. This is similar to our observations on AICAR-mediated inhibition of the peroxisome proliferator activated receptor γ translation in the absence of its conversion to ZMP34. Interestingly, mTORC1 inhibition induced either by rapamycin or AMPK activators is inferior to AICAR in alleviating palmitate-induced ER stress responses, arguing that the potency of AICAR is likely to represent a combination of transcriptional and translational effects.…”

Section: Discussionsupporting

confidence: 89%

AMPK-independent inhibition of human macrophage ER stress response by AICAR

Boß

Newbatt

Gupta

et al. 2016

Sci Rep

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Obesity-associated insulin resistance is driven by inflammatory processes in response to metabolic overload. Obesity-associated inflammation can be recapitulated in cell culture by exposing macrophages to saturated fatty acids (SFA), and endoplasmic reticulum (ER) stress responses essentially contribute to pro-inflammatory signalling. AMP-activated protein kinase (AMPK) is a central metabolic regulator with established anti-inflammatory actions. Whether pharmacological AMPK activation suppresses SFA-induced inflammation in a human system is unclear. In a setting of hypoxia-potentiated inflammation induced by SFA palmitate, we found that the AMP-mimetic AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) potently suppressed upregulation of ER stress marker mRNAs and pro-inflammatory cytokines. Furthermore, AICAR inhibited macrophage ER stress responses triggered by ER-stressors thapsigargin or tunicamycin. Surprisingly, AICAR acted independent of AMPK or AICAR conversion to 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate (ZMP) while requiring intracellular uptake via the equilibrative nucleoside transporter (ENT) ENT1 or the concentrative nucleoside transporter (CNT) CNT3. AICAR did not affect the initiation of the ER stress response, but inhibited the expression of major ER stress transcriptional effectors. Furthermore, AICAR inhibited autophosphorylation of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), while activating its endoribonuclease activity in vitro. Our results suggest that AMPK-independent inhibition of ER stress responses contributes to anti-inflammatory and anti-diabetic effects of AICAR.

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Section: Discussionsupporting

confidence: 89%

AMPK-independent inhibition of human macrophage ER stress response by AICAR

Boß

Newbatt

Gupta

et al. 2016

Sci Rep

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“…In IL-4-treated macrophages, we analyzed the expression of several PPAR␥ target genes, such as fatty acid binding protein 4 (FABP4), lipoprotein lipase, and CD36. As shown previously, these genes are induced PPAR␥-dependently during monocyte-to-macrophage differentiation (26). IL-4 did not increase the mRNA expression of the PPAR␥ targets CD36 and lipoprotein lipase in fully differentiated macrophages, whereas PPAR␥ mRNA tended to increase, but this did not reach statistical significance (Fig.…”

Section: Resultssupporting

confidence: 70%

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

Namgaladze

Snodgrass

Angioni

et al. 2015

Journal of Biological Chemistry

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Background: How AMP-activated protein kinase (AMPK) influences IL-4-induced human macrophage polarization is not completely understood. Results: AMPK prevents arachidonate 15-lipoxygenase induction by IL-4 and abolishes the formation of 15-lipoxygenase arachidonic acid metabolites. Conclusion: AMPK activation promotes an anti-inflammatory phenotype in IL-4-stimulated macrophages by reducing arachidonate 15-lipoxygenase expression. Significance: This study supports an anti-inflammatory effect of AMPK activation.

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“…These results indicate that although AMPK-1a phosphorylation status plays a crucial role during the PMA-induced monocyte-to-macrophage differentiation process, alterations in AMPK-1a activity alone are not sufficient to regulate the differentiation process. This unexpected result led us to search for other signaling pathways responsible for monocyte differentiation that are Induction of peroxisome proliferator-activated receptor (PPAR)-g expression and LPL activity is a common feature during monocyte and adipocyte differentiation (20,21). Activation of c-Jun N-terminal kinase (JNK) plays a central role in IL-1b induction during monocyte differentiation (22).…”

Section: Inactivation Of Ampk-1a Phosphorylation Promotes Monocyte-tomentioning

confidence: 99%

Metformin Inhibits Monocyte-to-Macrophage Differentiation via AMPK-Mediated Inhibition of STAT3 Activation: Potential Role in Atherosclerosis

et al. 2014

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Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by promoting an inflammatory environment within the vessel wall. In this study, we investigated the molecular mechanisms responsible for monocyte-to-macrophage differentiation and, subsequently, the effect of metformin in regressing angiotensin II (Ang-II)-mediated atheromatous plaque formation in ApoE 2/2 mice. AMPK activity was dose and time dependently downregulated during phorbol myristate acetate (PMA)-induced monocyteto-macrophage differentiation, which was accompanied by an upregulation of proinflammatory cytokine production. Of note, AMPK activators metformin and AICAR significantly attenuated PMA-induced monocyteto-macrophage differentiation and proinflammatory cytokine production. However, inhibition of AMPK activity alone by compound C was ineffective in promoting monocyte-to-macrophage differentiation in the absence of PMA. On the other hand, inhibition of c-Jun N-terminal kinase activity inhibited PMA-induced inflammation but not differentiation, suggesting that inflammation and differentiation are independent events. In contrast, inhibition of STAT3 activity inhibited both inflammation and monocyte-to-macrophage differentiation. By decreasing STAT3 phosphorylation, metformin and AICAR through increased AMPK activation caused inhibition of monocyte-to-macrophage differentiation.Metformin attenuated Ang-II-induced atheromatous plaque formation and aortic aneurysm in ApoE 2/2 mice partly by reducing monocyte infiltration. We conclude that the AMPK-STAT3 axis plays a pivotal role in regulating monocyte-to-macrophage differentiation and that by decreasing STAT3 phosphorylation through increased AMPK activity, AMPK activators inhibit monocyte-tomacrophage differentiation.

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AICAR inhibits PPARγ during monocyte differentiation to attenuate inflammatory responses to atherogenic lipids

Abstract: Inhibition of PPARγ-dependent gene expression during monocyte differentiation may contribute to an AICAR-elicited macrophage phenotype characterized by reduced inflammatory responses to modified lipoproteins and saturated fatty acids.

Cited by 26 publications

References 42 publications

AMPK-independent inhibition of human macrophage ER stress response by AICAR

AMPK-independent inhibition of human macrophage ER stress response by AICAR

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

Metformin Inhibits Monocyte-to-Macrophage Differentiation via AMPK-Mediated Inhibition of STAT3 Activation: Potential Role in Atherosclerosis

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