Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-activated Protein Kinase

Abstract

Evidence accumulated over the past several years indicates that the AMP-activated protein kinase (AMPK) 2 may be a therapeutic target for treating insulin resistance and type 2 diabetes (1). AMPK is a heterotrimeric protein formed by an ␣ subunit, which contains the catalytic activity, and by the ␤ and ␥ regulatory subunits important in maintaining stability of the heterotrimer complex (2). AMPK belongs to a family of energy-sensing enzymes functioning as a "fuel gauge" that monitors changes in the energy status of a cell (3, 4). When activated, AMPK shuts down anabolic pathways and promotes catabolism in response to an elevated AMP/ATP ratio by down-regulating the activity of several key enzymes of intermediary metabolism (4). Two primary acute consequences of AMPK activation are 1) an increase in glucose uptake by induction of glucose 4 transporter microvesicle cytoplasm to membrane translocation and fusion and 2) an increase in fatty acid oxidation by phosphorylation and inactivation of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (5). Therefore, the AMPK signal pathways are thought to play a central role in the regulation of cellular glucose and lipid homeostasis. The control of AMPK activity is complex, and the classic view is that AMPK is activated allosterically by an increase in the intracellular AMP/ATP ratios and/or by the phosphorylation of threonine 172 within the ␣ subunit. Several protein kinases responsible for this phosphorylation have been identified. They include Peutz-Jeghers syndrome kinase LKB1 (LKB1) (6), and the Ca 2ϩ /calmodulin-dependent protein kinase kinase (7). Protein phosphorylation signal transduction systems are balanced and regulated delicately by both phosphatase and kinase. Since AMPK is activated by (a) protein kinase(s) at the threonine 172 residue, one can easily assume that AMPK can be regulated negatively by (a) serine/threonine phosphatase(s). To date, a wide range of physiological stressors, pharmacological agents, and hormones associated with increase in the intracellular AMP/ATP ratios have been demonstrated to activate AMPK (8). AMPK is also thought to be regulated by glycogen (9), which is the major cellular storage form of carbohydrates and thus, an additional indicator of cellular energy status. Lipids are the other major energy source for cellular metabolism. Recent studies (10, 11) in heart and liver have revealed that AMPK may be sensitive to the "lipid status" of a cell, and activation may be influenced by intracellular fatty BSA, bovine serum albumin; eNOS, endothelial nitric-oxide synthase; LKB1, Peutz-Jeghers syndrome kinase LKB1; OA, okadaic acid; ONOO Ϫ , peroxynitrite; VSMC, vascular smooth muscle cell; siRNA, short interference RNA; FFA, free fatty acid; EBM, endothelial basal medium; 2-BrP, 2-bromopalmitate; HFD, high fat diet; PP2C, protein phosphatase 2C.

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

“…As far as we know, this is the first observation that lithium affects phosphorylation levels of AMPK. It has been reported that lithium inhibits PP2A activity [20,21], which has been shown to regulate phosphorylation of AMPK [31]. The observed effects of lithium on AMPK may also be related to the neuroprotective effects of lithium because AMPK activation is connected to cell survival in several systems [32][33][34].…”

Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation

“…The other mechanism is the inhibition of AMPK dephosphorylation by protein phosphatases [25,30] . In cell-free systems, protein phosphatase-2A and protein phosphatase-2C (PP2A/PP2C) dephosphorylate AMPK at Thr172 after binding to the threonine residue of AMPK, and AMP could inhibit this reaction by preventing this binding, which could increase the activity of AMPK [25,30,31] . Therefore, AMP activates AMPK by causing allosteric activation of AMPK as well as by making AMPK a Here, we showed that APS increased the cellular AMP levels and the AMP:ATP ratio in L6 myotubes, which may provide a mechanistic explanation for the activation of AMPK by APS.…”

Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism

“…Furthermore, saturated fatty acids, which may accumulate in livers of fructose-fed rats due to the increased synthesis and reduced oxidation, activate PP2A. 39 PP2A activity has also been implicated in repression of PPAR␣ gene expression, 40 and inhibition of Akt and AMPK activities. [39][40][41] All these effects could increase the hepatic metabolic derangements induced by fructose.…”

“…39 PP2A activity has also been implicated in repression of PPAR␣ gene expression, 40 and inhibition of Akt and AMPK activities. [39][40][41] All these effects could increase the hepatic metabolic derangements induced by fructose. The fact that fructose is mainly metabolized in liver, while glucose is distributed to and metabolized in other body tissues, can explain why, despite also being metabolized to xylulose-5-phosphate, 30 glucose does not induce hyperleptinemia and hepatic leptin resistance when ingested at an equivalent amount of energy as fructose.…”