Down‐regulation of Pyruvate Dehydrogenase Phosphatase in Obese Subjects is a Defect that Signals Insulin Resistance

Piccinini, Marco; Mostert, M.; Alberto, G; Ramondetti, Cristina; Novi, Rosa F.; Dalmasso, Paola; Rinaudo, M.

doi:10.1038/oby.2005.76

Cited by 17 publications

(11 citation statements)

References 63 publications

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“…Insulin also increases the affinity of PDP1 for Mg 2+ , stimulating its phosphatase activity (56) and thereby increasing the activity of the mitochondrial pyruvate dehydrogenase complex. Interestingly, PDP1 from obese subjects is less active and has reduced affinity for Mg 2+ (57). …”

Section: Discussionmentioning

confidence: 99%

Binding of a Third Metal Ion by the Human Phosphatases PP2Cα and Wip1 Is Required for Phosphatase Activity

et al. 2013

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The PPM phosphatases require millimolar concentrations of Mg2+ or Mn2+ to activate phosphatase activity in vitro. The human phosphatases PP2Cα (PPM1A) and Wip1 (PPM1D) differ in their physiological function, substrate specificity, and apparent metal affinity. A crystallographic structure of PP2Cα shows only two metal ions in the active site. However, recent structural studies of several bacterial PP2C phosphatases have indicated three metal ions in the active site. Two residues that coordinate the third metal ion are highly conserved, suggesting that human PP2C phosphatases may also bind a third ion. Here, isothermal titration calorimetry analysis of Mg2+ binding to PP2Cα distinguished binding of two ions to high affinity sites from the binding of a third ion with a millimolar affinity, similar to the apparent metal affinity required for catalytic activity. Mutational analysis indicated that Asp239 and either Asp146 or Asp243 was required for low-affinity binding of Mg2+, but that both Asp146 and Asp239 were required for catalysis. Phosphatase activity assays in the presence of MgCl2, MnCl2, or mixtures of the two, demonstrate high phosphatase activity toward a phosphopeptide substrate when Mg2+ was bound to the low-affinity site, whether Mg2+ or Mn2+ ions were bound to the high affinity sites. Mutation of the corresponding putative third metal ion-coordinating residues of Wip1 affected catalytic activity similarly both in vitro and in human cells. These results suggest that phosphatase activity toward phosphopeptide substrates by PP2Cα and Wip1 requires the binding of a Mg2+ ion to the low-affinity site.

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Section: Discussionmentioning

confidence: 99%

Binding of a Third Metal Ion by the Human Phosphatases PP2Cα and Wip1 Is Required for Phosphatase Activity

et al. 2013

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“…Piccinini et al (36) reported downregulation of lymphocyte PDP activity in obese humans. Also, administration of agents that improve glucose homeostasis and insulin sensitivity also increases hepatic PDP activity in rodent models of type-2 diabetes (8,9).…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle type comparison of pyruvate dehydrogenase phosphatase activity and isoform expression: effects of obesity and endurance training

LeBlanc¹,

Mulligan²,

Antolić³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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SJ. Skeletal muscle type comparison of pyruvate dehydrogenase phosphatase activity and isoform expression: effects of obesity and endurance training. Am J Physiol Regul Integr Comp Physiol 295: R1224 -R1230, 2008. First published August 20, 2008 doi:10.1152/ajpregu.90320.2008.-Pyruvate dehydrogenase (PDH) plays an important role in regulating carbohydrate metabolism in skeletal muscle. PDH is activated by PDH phosphatase (PDP) and deactivated by PDH kinase (PDK). Obesity has a large negative impact on skeletal muscle carbohydrate metabolism, whereas endurance training has been shown to improve regulatory control of skeletal muscle carbohydrate metabolism, more so when coupled with obesity. A majority of this literature has focused on PDK, with little information available on PDP. To determine the relative role of PDP in regulating skeletal muscle PDH activity with obesity and endurance training, obese and lean Zucker rats remained sedentary or were endurance trained (1 h/day, 5 days/wk) for a period of 8 wk. Soleus, red gastrocnemius, (RG), and white gastrocnemius (WG) muscles were sampled after the training period. The main findings were 1) obesity resulted in a 46% decrease in PDP activity expressed per milligram extracted mitochondrial protein only in RG, while PDP isoform content was unchanged; 2) 8 wk of endurance training led to a significant 1.4 -2.2-fold increase in PDP activity of all muscle examined from obese rats, and the concomitant increase in PDP1 protein was only seen in soleus and RG; 3) 8 wk of endurance training led to a trending 1.4 -2.2-fold increase in PDP activity of all muscle examined from obese rats, and the concomitant increase in PDP1 protein was only seen in soleus and RG; and 4) PDP2 protein content was not affected by obesity or training. These results suggest that decreased PDP activity in oxidative skeletal muscles may play a role in the impairment of carbohydrate metabolism in obese rats, which is reversible with endurance training. PDP1 and 2; carbohydrate oxidation; exercise PYRUVATE DEHYDROGENASE (PDH) is a key component to glucose homeostasis, as it is the first nonreversible step in mitochondrial glucose oxidation. It is a complex enzyme with many copies of the catalytic subunits and proteins (E1␣, E1␤, E2, E3, and E3 binding protein), as well as its associated regulatory kinase and phophatase enzymes. Decreased carbohydrate flux through PDH is mediated through its phosphorylation and deactivation via PDH kinase (PDK; as reviewed by Refs. 7 and 42). The activation of PDH, via dephosphorylation by PDH phosphatase (PDP), promotes carbohydrate oxidation. The complexity of PDH control by PDK and PDP is enhanced by the presence of multiple isoforms, four PDK [PDK1-4 (4)] and two PDP [PDP1 and 2 (18)]. The two PDP isoforms are unique in their skeletal muscle type distribution and allosteric regulators. PDP1 is the predominant isoform expressed in skeletal muscle, with ϳ2.5 times more found in red gastrocnemius (RG) compared with soleus and white gastrocnemius [WG; (26)] and is ...

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“…Protein phosphatase 2C, magnesium-dependent, catalytic subunit is a mitochondrial enzyme regulated by insulin. (94) Niemann-Pick disease, type C1 is a lysosomal membrane protein involved in cholesterol trafficking, (95) and, most importantly, in drug resistance by its drug efflux and sequestration. (96) The genes downregulated in the wt-PAI-1-expressing MDA-MB-435 cells were less numerous ( Table 2).…”

Section: Cell Migration and Invasionmentioning

confidence: 99%

Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor‐1 cycle

et al. 2007

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SummaryPlasminogen activator inhibitor-1 (PAI-1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI-1 should be beneficial in down-regulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI-1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the "PAI-1 paradox". Many factors are responsible for the upregulation of PAI-1 in the tumor micro-environment. We hypothesize that there is a breast cancer predisposition to a more aggressive stage when PAI-1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyper-insulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the "PAI-1 cycle". Sustained by MetS, adipocytokines alter PAI-1 expression to promote angio-genesis, tumor-cell migration and procoagulant micro-particle formation from endothelial cells, which generates thrombin and further propagates PAI-1 synthesis. All of these factors culminate in a chemotherapy-resistant breast tumor microenvironment. The PAI-1 cycle may partly explain the PAI-1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI-1 and how an increased level of PAI-1 can be linked to a poor prognosis.

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Down‐regulation of Pyruvate Dehydrogenase Phosphatase in Obese Subjects is a Defect that Signals Insulin Resistance

Cited by 17 publications

References 63 publications

Binding of a Third Metal Ion by the Human Phosphatases PP2Cα and Wip1 Is Required for Phosphatase Activity

Binding of a Third Metal Ion by the Human Phosphatases PP2Cα and Wip1 Is Required for Phosphatase Activity

Skeletal muscle type comparison of pyruvate dehydrogenase phosphatase activity and isoform expression: effects of obesity and endurance training

Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor‐1 cycle

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