Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Oct;24(10):481-7.
doi: 10.1016/j.tem.2013.06.002. Epub 2013 Jul 19.

AMPK: Mediating the Metabolic Effects of Salicylate-Based Drugs?

Affiliations
Free PMC article

AMPK: Mediating the Metabolic Effects of Salicylate-Based Drugs?

Gregory R Steinberg et al. Trends Endocrinol Metab. .
Free PMC article

Abstract

Salicylates are among the oldest medicinal compounds known to humans, and have been used to reduce fever, pain, and inflammation. The major oral salicylates are aspirin and salsalate, both of which are rapidly metabolized to salicylate in vivo. Owing to its acetyl group, aspirin irreversibly inhibits cyclo-oxygenases and thus blocks platelet aggregation, whereas salsalate has been used for treatment of inflammatory diseases such as rheumatoid arthritis. Recently, beneficial effects of salicylates in type 2 diabetes and cancer have been proposed. This has led to renewed interest in understanding how these simple molecules have such diverse and multifaceted effects. Here we discuss the idea that AMP-activated protein kinase (AMPK) might mediate some effects of salicylate-based drugs, particularly by modulating cellular metabolism.

Keywords: AMPK; aspirin; cancer; diabetes; inflammation; salicylate.

Figures

Figure 1
Figure 1. Structures of salicylate-based natural products (top) and synthetic derivatives (bottom).
Figure 2
Figure 2. Effects of salicylate on lipid metabolism mediated by AMPK.
Salicylate activates AMPK in both hepatocytes and adipocytes. In hepatocytes, AMPK activation causes phosphorylation of the ACC1 and ACC2 isoforms of acetyl-CoA carboxylase, lowering malonyl-CoA. This inhibits fatty acid synthesis, while also promoting fatty acid oxidation by relieving inhibition of carnitine-palmitoyl-CoA transferase-1 (CPT1), thus helping to generate ATP. In the longer term, AMPK promotes oxidative metabolism by increasing expression of oxidative enzymes (e.g. those marked with green asterisks), while down-regulating lipogenic enzymes (red asterisks). In adipocytes, AMPK activation inhibits fatty acid synthesis (not shown) by phosphorylation of ACC1, and triacylglycerol (TAG) synthesis by inactivation of glycerol phosphate acyl transferase (GPAT), while inhibiting TAG breakdown by phosphorylation of hormone-sensitive lipase (HSL), the enzyme that converts diacylglycerol (DAG) to monoacylglycerol (MAG). The latter effect reduces release of fatty acids into the bloodstream (lipolysis). The net effect of these changes is that salicylate reduces the accumulation of lipids in hepatocytes, enhancing insulin sensitivity.
Figure 3
Figure 3. Proposed mechanisms by which AMPK activators exert a cytostatic effect and oppose the metabolic changes occurring in proliferating cells.
Salicylate or A-769662 enter the cell and activate AMPK complexes containing the β1 subunit. Metformin, a cation, enters by transport catalyzed by the organic cation transporter 1 (OCT1), and accumulates in mitochondria due to the electrical gradient across the inner membrane. Here metformin inhibits Complex I and hence ATP synthesis, causing a build-up of ADP and AMP in the cytoplasm. This is detected by the AMPK-γ subunit, leading to increased Thr172 phosphorylation and allosteric activation. The activated AMPK then triggers cell cycle checkpoints through increased p53 activity, activates autophagy via ULK1 phosphorylation, and inhibits the mechanistic target-of-rapamycin complex-1 (mTORC1). The latter effect inhibits translation of proteins required for rapid cell growth, including ribosomal proteins and hypoxia-inducible factor-1α (HIF-1α), with the latter being required for rapid glucose uptake and glycolysis (the Warburg effect). At the same time, AMPK activates peroxisomal proliferator-activated receptor-γ co-activator-1α (PGC-1α), increasing mitochondrial biogenesis and expression of mitochondrial oxidative enzymes. Thus, the cell switches from the glycolytic metabolism typical of a proliferating cell to the oxidative metabolism more typical of a quiescent cell.

Similar articles

See all similar articles

Cited by 26 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback