scholarly journals Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone

2003 ◽  
Vol 369 (3) ◽  
pp. 687-695 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Nicholas D. SMITH ◽  
Mary C. SUGDEN
Keyword(s):  
Thyroid Hormone ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Hormone Receptors ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Cpt I ◽  
Fat Feeding

Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-α (PPARα). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-α. Heterodimerization partners for retinoid X receptors (RXRs) include PPARα and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-α activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARα activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARα, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARα or TR with the RXR receptor and that effects of PPARα activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.

scholarly journals Evaluation of the role of peroxisome-proliferator-activated receptor α in the regulation of cardiac pyruvate dehydrogenase kinase 4 protein expression in response to starvation, high-fat feeding and hyperthyroidism

2002 ◽  
Vol 364 (3) ◽  
pp. 687-694 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Nicholas D. SMITH ◽  
Karen BULMER ◽  
Teresa HOPKINS ◽  
Geoffrey F. GIBBONS ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Fold Increase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor

Inactivation of cardiac pyruvate dehydrogenase complex (PDC) after prolonged starvation and in response to hyperthyroidism is associated with enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4. The present study examined the potential role of peroxisome-proliferator-activated receptor α (PPARα) in adaptive modification of cardiac PDK4 protein expression after starvation and in hyperthyroidism. PDK4 protein expression was analysed by immunoblotting in homogenates of hearts from fed or 48h-starved rats, rats rendered hyperthyroid by subcutaneous injection of tri-iodothyronine and a subgroup of euthyroid rats maintained on a high-fat/low-carbohydrate diet, with or without treatment with the PPARα agonist WY14,643. In addition, PDK4 protein expression was analysed in hearts from fed, 24h-starved or 6h-refed wild-type or PPARα-null mice. PPARα activation by WY14,643 in vivo over the timescale of the response to starvation failed to up-regulate cardiac PDK4 protein expression in rats maintained on standard diet (WY14,643, 1.1-fold increase; starvation, 1.8-fold increase) or influence the cardiac PDK4 response to starvation. By contrast, PPARα activation by WY14,643 in vivo significantly enhanced cardiac PDK4 protein expression in rats maintained on a high-fat diet, which itself increased cardiac PDK4 protein expression. PPARα deficiency did not abolish up-regulation of cardiac PDK4 protein expression in response to starvation (2.9-fold increases in both wild-type and PPARα-null mice). Starvation and hyperthyroidism exerted additive effects on cardiac PDK4 protein expression, but PPARα activation by WY14,643 did not influence the response of cardiac PDK4 protein expression to hyperthyroidism in either the fed or starved state. Our data support the hypothesis that cardiac PDK4 protein expression is regulated, at least in part, by a fatty acid-dependent, PPARα-independent mechanism and strongly implicate a fall in insulin in either initiating or facilitating the response of cardiac PDK4 protein expression to starvation.

scholarly journals Coenzyme A–mediated degradation of pyruvate dehydrogenase kinase 4 promotes cardiac metabolic flexibility after high-fat feeding in mice

2018 ◽  
Vol 293 (18) ◽  
pp. 6915-6924 ◽  
Author(s):  
Christopher Schafer ◽  
Zachary T. Young ◽  
Catherine A. Makarewich ◽  
Abdallah Elnwasany ◽  
Caroline Kinter ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Coenzyme A ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Flexibility ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Fat Feeding

Abstract TP268: Combination Therapy of Normobaric Oxygen With Hypothermia or Ethanol Modulates Pyruvate Dehydrogenase Complex in Thromboembolic Cerebral Ischemia

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Alexa Thibodeau ◽  
Lipeng Cai ◽  
Changya Peng ◽  
Xiaokun Geng ◽  
Vicki Diaz ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Tissue Type ◽  
Energy Regulation ◽  
Normobaric Oxygen ◽  
Expression Levels ◽  
Dehydrogenase Complex

Background and Hypothesis: Pyruvate Dehydrogenase Complex (PDH) is a brain mitochondrial matrix enzyme that is inactivated during stroke injury. PDH impairment after stroke can be particularly devastating given PDH’s critical role in the conversion from anaerobic to aerobic energy metabolism. In this study, we evaluated the restoration of oxidative metabolism by measuring reactive oxygen species (ROS) levels and energy regulation by characterizing modulation of PDH and its inhibitor, pyruvate dehydrogenase kinase (PDK), with therapeutic combination of normobaric oxygen (NBO) plus either hypothermia (Hypo) or ethanol (EtOH). Methods: Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occlusion induced with an autologous embolus, the more clinically relevant stroke model. One hour after occlusion, tissue-type plasminogen activator (t-PA) was administered alone or with NBO (60%), EtOH (1.0g/kg) or Hypo (33°C), either singly or in combination. PDH activity and ROS levels were measured at 3 and 24 hours after t-PA administration. Western blotting was used to detect PDH and PDK protein expression levels. Results: Administration of 60% NBO alone after reperfusion by t-PA treatment did not affect PDH activity. Under t-PA, compared to EtOH or Hypo alone, combined administration of NBO plus either EtOH or Hypo produced the greatest increases in PDH activity and protein expression levels, as well as the greatest decrease in PDK expression. Combination therapy also provided the most significant decline in ROS generation compared to any monotherapeutic approach. Conclusions: Reperfusion with t-PA followed by 60% NBO improves the efficacy of EtOH or Hypo in neuroprotection by ameliorating oxidative injury and improving metabolic regulation with PDH. Comparable neuroprotective effects were found when treating with either EtOH or Hypo, suggesting a similar mechanism and the possibility of substituting EtOH for Hypo in the clinical setting.

scholarly journals Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor α (PPARα)

2002 ◽  
Vol 366 (3) ◽  
pp. 839-846 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Mary C. SUGDEN
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Skeletal Muscles ◽  
Pyruvate Dehydrogenase Kinase ◽  
Glucose Disposal ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anterior Tibialis

In insulin deficiency, increased lipid delivery and oxidation suppress skeletal-muscle glucose oxidation by inhibiting pyruvate dehydrogenase complex (PDC) activity via enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4, which phosphorylates (and inactivates) PDC. Signalling via peroxisome-proliferator-activated receptor α (PPARα) is an important component of the mechanism enhancing hepatic and renal PDK4 protein expression. Activation of PPARα in gastrocnemius, a predominantly fast glycolytic (FG) muscle, also increases PDK4 expression, an effect that, if extended to all muscles, would be predicted to drastically restrict whole-body glucose disposal. Paradoxically, chronic activation of PPARα by WY14,643 treatment improves glucose utilization by muscles of insulin-resistant high-fat-fed rats. In the resting state, oxidative skeletal muscles are quantitatively more important for glucose disposal than FG muscles. We evaluated the participation of PPARα in regulating PDK4 protein expression in slow oxidative (SO) skeletal muscle (soleus) and fast oxidative-glycolytic (FOG) skeletal muscle (anterior tibialis) containing a high proportion of oxidative fibres. In the fed state, acute (24h) activation of PPARα by WY14,643 in vivo failed to modify PDK4 protein expression in soleus, but modestly enhanced PDK4 protein expression in anterior tibialis. Starvation enhanced PDK4 protein expression in both muscles, with the greater response in anterior tibialis. WY14,643 treatment in vivo during starvation did not further enhance upregulation of PDK4 protein expression in either muscle type. Enhanced PDK4 protein expression after starvation was retained in SO and FOG skeletal muscles of PPARα-deficient mice. Our data indicate that PDK4 protein expression in oxidative skeletal muscle is regulated by a lipid-dependent mechanism that is not obligatorily dependent on signalling via PPARα.

scholarly journals Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Yves Lecarpentier ◽  
Victor Claes ◽  
Alexandre Vallée ◽  
Jean-Louis Hébert
Keyword(s):  
Type 2 Diabetes ◽  
Colon Cancer ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Ppar Gamma ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Beta Catenin ◽  
Canonical Wnt

In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.

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