AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern
ABSTRACT The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell-cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines.
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ABSTRACT: AMP kinase is a heterotrimeric serine/threonine protein kinase that regulates a number of metabolic processes, including lipid biosynthesis and metabolism. AMP kinase activity is regulated by phosphorylation, and the kinases involved have been uncovered. The particular phosphatases counteracting these kinases remain elusive. Here we discovered that the protein phosphatase 2A heterotrimer, PP2A,(Ppp2r2d,), regulates the phosphorylation state of AMP kinase by dephosphorylating Thr172, a residue that activates kinase activity when phosphorylated. Co-immunoprecipitation and co-localization studies indicated that PP2AP(pp2r2d) directly interacted with AMP kinase. PP2A(Ppp2r2d) dephosphorylated Thr172 in rat aortic and human vascular smooth muscle cells. This was a correlation between decreased phosphorylation and decreased acetyl-CoA carboxylase Acc1, and SREBP1c-dependent gene expression. PP2A(Ppp2r2d) protein expression was up regulated in the aortas of mice fed a high fat diet, and the increased expression correlated with increased blood lipid levels. Finally, we found that the aortas of mice fed a high fat diet had an elevated protein level of PP2APpp2r2d, decreased AMP kinase Thr172 phosphorylation, and contained an Ampk-PP2AP(pp2r2d) complex. Thus, PP2AP(pp2r2d) may antagonize the aortic AMP kinase activity necessary for maintaining normal aortic lipid metabolism. Inhibiting PP2AP(pp2r2d) or activating AMP kinase represents potential pharmacological treatments for many lipid-related diseases. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.Journal of Biological Chemistry 02/2015; DOI:10.1074/jbc.M114.626259 · 4.60 Impact Factor
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ABSTRACT: Recently, AMP-activated protein kinase (AMPK) has emerged as a key regulator of energy balance at cellular and whole-body levels. Due to the involvement in multiple signaling pathways, AMPK efficiently controls ATP-consuming/ATP-generating processes to maintain energy homeostasis under stress conditions. Loss of the kinase activity or attenuation of its expression leads to a variety of metabolic disorders and increases cancer risk. In this review, we discuss recent findings on the structure of AMPK, its activation mechanisms, as well as the consequences of its targets in regulation of metabolism. Particular attention is given to low-molecular-weight compounds that activate or inhibit AMPK; the perspective of therapeutic use of such modulators in treatment of several common diseases is discussed.Biochemistry (Moscow) 02/2015; 80(2):127-144. DOI:10.1134/S0006297915020017 · 1.35 Impact Factor
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ABSTRACT: Sonic hedgehog (Shh) pathway has been reported to protect cardiomyocytes in myocardial infarction (MI), but the underlying mechanism is not clear. Here, we provide evidence that Shh pathway induces cardiomyocytes survival through AMP-activated protein kinase-dependent autophagy. Shh pathway agonist SAG increased the expression of LC3-II, and induced the formation of autophagosomes in cultured H9c2 cardiomyocytes under oxygen glucose deprivation (OGD) 1 h and 4 h. Moreover, SAG induced a profound AMP-activated protein kinase (AMPK) activation, and then directly phosphorylated and activated the downstream autophagy initiator Ulk1, independent of the autophagy suppressor mammalian target of rapamycin (mTOR) complex 1. Taken together, our results have shown that Shh activates AMPK-dependent autophagy in cardiomyocytes under OGD, suggesting a role of autophagy in Shh-induced cellular protection.Biochemical and Biophysical Research Communications 01/2015; DOI:10.1016/j.bbrc.2015.01.006 · 2.28 Impact Factor