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 More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of 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, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to 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.

Links

Publisher Full Text

Authors

Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG

Institution

Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

Source

Science (New York, N.Y.) 336:6083 2012 May 18 pg 918-22

MeSH

AMP-Activated Protein Kinases
Amino Acid Substitution
Animals
Aspirin
Binding Sites
Carbohydrate Metabolism
Cell Line
Enzyme Activation
Enzyme Activators
HEK293 Cells
Humans
Lipid Metabolism
Liver
Mice
Mice, Knockout
Mutation
Oxygen Consumption
Phosphorylation
Pyrones
Rats
Salicylates
Thiophenes

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22517326