The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

Simon A Hawley; Morgan D Fullerton; Fiona A Ross; Jonathan D Schertzer; Cyrille Chevtzoff; Katherine J Walker; Mark W Peggie; Darya Zibrova; Kevin A Green; Kirsty J. Mustard; Bruce E Kemp; Kei Sakamoto; Gregory R Steinberg; D Grahame Hardie

doi:10.1126/science.1215327

The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

Simon A Hawley, Morgan D Fullerton, Fiona A Ross, Jonathan D Schertzer, Cyrille Chevtzoff, Katherine J Walker, Mark W Peggie, Darya Zibrova, Kevin A Green, Kirsty J. Mustard, Bruce E Kemp, Kei Sakamoto, Gregory R Steinberg, D Grahame Hardie (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

610 Citations (Scopus)

Abstract

Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo. At concentrations reached in plasma following administration of salsalate, or aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator, A-769662, to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, Thr172. In AMPK knockout mice, effects of salicylate to increase fat utilization and lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.

Original language	English
Pages (from-to)	918-922
Number of pages	5
Journal	Science
Volume	336
Issue number	6083
Early online date	19 Apr 2012
DOIs	https://doi.org/10.1126/science.1215327
Publication status	Published - 18 May 2012

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title = "The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase",

abstract = "Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo. At concentrations reached in plasma following administration of salsalate, or aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator, A-769662, to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, Thr172. In AMPK knockout mice, effects of salicylate to increase fat utilization and lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.",

author = "Hawley, {Simon A} and Fullerton, {Morgan D} and Ross, {Fiona A} and Schertzer, {Jonathan D} and Cyrille Chevtzoff and Walker, {Katherine J} and Peggie, {Mark W} and Darya Zibrova and Green, {Kevin A} and Mustard, {Kirsty J.} and Kemp, {Bruce E} and Kei Sakamoto and Steinberg, {Gregory R} and Hardie, {D Grahame}",

note = "Acknowledgments: D.G.H. was supported by a Programme Grant (080982) from the Wellcome Trust and K.S. by the Medical Research Council. D.G.H. and K.S. were also funded by the companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck Serono, and Pfizer) supporting the Division of Signal Transduction Therapy, Univ. of Dundee. The studies were also supported by grants and fellowship from the Canadian Institutes of Health Research (CIHR) (M.D.F. and G.R.S.), the Canadian Diabetes Association (J.D.S. and G.R.S.), the National Health and Medical Research Council of Australia (G.R.S. and B.E.K.), and the Australian Research Council and the Victorian Government{\textquoteright}s Operational Infrastructure Support Program (B.E.K.). ",

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AU - Chevtzoff, Cyrille

AU - Walker, Katherine J

AU - Peggie, Mark W

AU - Zibrova, Darya

AU - Green, Kevin A

AU - Mustard, Kirsty J.

AU - Kemp, Bruce E

AU - Sakamoto, Kei

AU - Steinberg, Gregory R

AU - Hardie, D Grahame

N1 - Acknowledgments: D.G.H. was supported by a Programme Grant (080982) from the Wellcome Trust and K.S. by the Medical Research Council. D.G.H. and K.S. were also funded by the companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck Serono, and Pfizer) supporting the Division of Signal Transduction Therapy, Univ. of Dundee. The studies were also supported by grants and fellowship from the Canadian Institutes of Health Research (CIHR) (M.D.F. and G.R.S.), the Canadian Diabetes Association (J.D.S. and G.R.S.), the National Health and Medical Research Council of Australia (G.R.S. and B.E.K.), and the Australian Research Council and the Victorian Government’s Operational Infrastructure Support Program (B.E.K.).

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N2 - Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo. At concentrations reached in plasma following administration of salsalate, or aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator, A-769662, to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, Thr172. In AMPK knockout mice, effects of salicylate to increase fat utilization and lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.

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The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

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New research highlights benefits of old medicine

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The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

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New research highlights benefits of old medicine

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