AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase.
The utility of C-reactive protein (CRP) as an independent risk factor for vascular events may be attributable, at least in part, to a direct adverse impact of CRP on endothelial function. In particular, modestly elevated concentrations of CRP have been shown to decrease the expression of the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells; the implication of this for vascular health is evident. Strategies for decreasing elevated CRP include administration of statins, thiazolidinediones, and metformin; moderate alcohol consumption and appropriate weight loss are also helpful in this regard. Metformin's antidiabetic efficacy is now known to reflect activation of AMP-activated kinase (AMPK); AMPK can stimulate eNOS, which is expressed in hepatocytes. A recent study shows that nitric oxide suppresses the activation of Stat3 by interleukin-6 in hepatocytes; Stat3 is crucial for the IL-6-mediated induction of CRP and various other acute phase reactants. Thus, it is proposed that metformin--or AMPK---inhibits hepatic CRP production by boosting hepatic nitric oxide synthesis, which in turn impedes Stat3 activation and CRP transcription. This hypothesis should be readily testable in cultured hepatocytes. Although the impact of metformin on plasma IL-6 levels has not been reported, the possibility that AMPK activation could influence adipocyte secretion of this cytokine also merits scrutiny.
McCarty
Mark F
MF
NutriGuard Research, 1051 Hermes Avenue, Encinitas, CA 92024, USA. mccarty@pantox.com
D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000378:metabolism; D002097:C-Reactive Protein / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D015850:Interleukin-6; D009097:Multienzyme Complexes; D002097:C-Reactive Protein; D008687:Metformin; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases