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Aspirin activates metabolic master switch.

Adenosine monophosphate activated protein kinase (AMPK) is a metabolic master switch and a primary target for those seeking to treat type II diabetes. A new paper in Science shows that AMPK can be directly activated by salicylate, the active ingredient in Aspirin.

Most drugs designed to act on AMPK do so by increasing levels of adenosine monophosphate (AMP) and adenosine diphosphate (ADP). These nucleotides accumulate when cells are stressed, such as during exercise and can trigger activation of AMPK. Only one drug, called A-769662, was known to activate AMPK by directly binding to the protein. "Clinical data on type II diabetic humans showed that when aspirin or salsalate (a salicylate precursor) were taken, there was a large drop in circulating free fatty acids," says Gregory Steinberg, associate professor in the Department of Medicine at McMaster University and one of the co-authors of the paper. "Since AMPK is important for regulating fatty acid metabolism, we pursued that angle," he says.

Experiments showed that salicylate did not impact levels of AMP or ADP. Consistent with this finding, salicylate was found to increase AMPK activity even in cells expressing a mutant form of AMPK that could not bind to AMP or ADP. In another experiment, salicylate was shown to have no effect on AMPK activity or fat oxidation in mice lacking the beta-1 subunit of AMPK, the putative binding site of A-769662. This suggests the mechanism for the two drugs is the same.

Steinberg cautions that the levels of salicylate used in the experiments are far higher than one would get from a regular aspirin; it remains to be seen if lower doses would have the same effect. Still, the discovery that a simple, well-understood drug acts on AM PK in a way that few others can is encouraging for diabetes treatment. "All the pharmaceutical companies have had drug programs trying to find direct activators of AMPK, so it's pretty ironic that there was one right under our nose the whole time," says Steinberg.
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Title Annotation:BIOCHEMISTRY
Author:Irving, Tyler
Publication:Canadian Chemical News
Date:Jun 1, 2012
Words:331
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