scholarly journals PDK2: An Underappreciated Regulator of Liver Metabolism

Livers ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 82-97
Author(s):  
Benjamin L. Woolbright ◽  
Robert A. Harris
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Mammalian Cells ◽  
Drug Targets ◽  
Pyruvate Dehydrogenase Complex ◽  
Liver Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Flexibility ◽  
Fed State ◽  
Disease States ◽  
Dehydrogenase Complex

Pyruvate metabolism is critical for all mammalian cells. The pyruvate dehydrogenase complex couples the pyruvate formed as the primary product of glycolysis to the formation of acetyl-CoA required as the primary substrate of the citric acid cycle. Dysregulation of this coupling contributes to alterations in metabolic flexibility in obesity, diabetes, cancer, and more. The pyruvate dehydrogenase kinase family of isozymes phosphorylate and inactive the pyruvate dehydrogenase complex in the mitochondria. This function makes them critical mediators of mitochondrial metabolism and drug targets in a number of disease states. The liver expresses multiple PDKs, predominantly PDK1 and PDK2 in the fed state and PDK1, PDK2, and PDK4 in the starved and diabetic states. PDK4 undergoes substantial transcriptional regulation in response to a diverse array of stimuli in most tissues. PDK2 has received less attention than PDK4 potentially due to the dramatic changes in transcriptional gene regulation. However, PDK2 is more responsive than the other PDKs to feedforward and feedback regulation by substrates and products of the pyruvate dehydrogenase complex. Although underappreciated, this makes PDK2 particularly important for the minute-to-minute fine control of the pyruvate dehydrogenase complex and a major contributor to metabolic flexibility. The purpose of this review is to characterize the underappreciated role of PDK2 in liver metabolism. We will focus on known biological actions and physiological roles as well as what roles PDK2 may play in disease states. We will also define current inhibitors and address their potential as therapeutic agents in the future.

scholarly journals Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

1998 ◽  
Vol 329 (1) ◽  
pp. 191-196 ◽  
Author(s):  
Melissa M. BOWKER-KINLEY ◽  
I. Wilhelmina DAVIS ◽  
Pengfei WU ◽  
A. Robert HARRIS ◽  
M. Kirill POPOV
Keyword(s):  
Tissue Distribution ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Synthetic Analogue ◽  
Complex Activity ◽  
Acetyl Coa ◽  
Tissue Specific ◽  
Specific Regulation ◽  
Dehydrogenase Complex

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified thus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was present in all tissues tested but the level was low in spleen and lung. The mRNA for PDK4 was predominantly expressed in skeletal muscle and heart. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent Ki values of the isoenzymes for the synthetic analogue of pyruvate, dichloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to respond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the activities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-CoA activated these isoenzymes nearly 200 and 300%. Under comparable conditions, isoenzyme PDK3 was almost completely unresponsive to NADH, and NADH plus acetyl-CoA caused inhibition rather than activation. Isoenzyme PDK4 was activated almost 2-fold by NADH, but NADH plus acetyl-CoA did not activate above the level seen with NADH alone. These results provide the first evidence that the unique tissue distribution and kinetic characteristics of the isoenzymes of PDK are among the major factors responsible for tissue-specific regulation of the pyruvate dehydrogenase complex activity.

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 Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex

2002 ◽  
Vol 366 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Alina TUGANOVA ◽  
Igor BOULATNIKOV ◽  
Kirill M. POPOV
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Kinase Activity ◽  
Pyruvate Dehydrogenase Complex ◽  
Tight Binding ◽  
Enzymic Activity ◽  
Pyruvate Dehydrogenase Kinase ◽  
Size Exclusion ◽  
Apparent Dissociation Constant ◽  
The Individual ◽  
Dehydrogenase Complex

Protein—protein interactions play an important role in the regulation of enzymic activity of pyruvate dehydrogenase kinase (PDK). It is generally believed that the binding of PDK to the inner lipoyl-bearing domain L2 of the transacetylase component E2 of pyruvate dehydrogenase complex largely determines the level of kinase activity. In the present study, we characterized the interaction between the individual isoenzymes of PDK (PDK1—PDK4) and monomeric L2 domain of human E2, as well as the effect of this interaction on kinase activity. It was found that PDK isoenzymes are markedly different with respect to their affinities for L2. PDK3 demonstrated a very tight binding, which persisted during isolation of PDK3—L2 complexes using size-exclusion chromatography. Binding of PDK1 and PDK2 was readily reversible with the apparent dissociation constant of approx. 10μM for both isoenzymes. PDK4 had a greatly reduced capacity for L2 binding (relative order PDK3>PDK1 = PDK2>PDK4). Monomeric L2 domain alone had very little effect on the activities of either PDK1 or PDK2. In contrast, L2 caused a 3-fold increase in PDK3 activity and approx. 37% increase in PDK4 activity. These results strongly suggest that the interactions between the individual isoenzymes of PDK and L2 domain are isoenzyme-specific and might be among the major factors that determine the level of kinase activity of particular isoenzyme towards the pyruvate dehydrogenase complex.

scholarly journals Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species

2012 ◽  
Vol 287 (42) ◽  
pp. 35153-35160 ◽  
Author(s):  
Thomas R. Hurd ◽  
Yvonne Collins ◽  
Irina Abakumova ◽  
Edward T. Chouchani ◽  
Bartlomiej Baranowski ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Oxygen Species ◽  
Complex Activity ◽  
Cycle Enzyme ◽  
Dehydrogenase Complex

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O2̇̄), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O2̇̄ production, such as may occur under nutrient excess and low ATP demand, the increase in O2̇̄ and H2O2 may provide feedback signals to modulate mitochondrial metabolism.

scholarly journals Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Sun Joo Lee ◽  
Ji Yun Jeong ◽  
Chang Joo Oh ◽  
Sungmi Park ◽  
Joon-Young Kim ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Direct Interaction ◽  
Pathologic Response ◽  
Pyruvate Dehydrogenase Kinase ◽  
Phosphate Homeostasis ◽  
Mortality And Morbidity ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Dehydrogenase Complex

Abstract Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.

scholarly journals The relationship between changes in lipid fuel availability and tissue fructose 2,6-bisphosphate concentrations and pyruvate dehydrogenase complex activities in the fed state

1988 ◽  
Vol 256 (3) ◽  
pp. 935-939 ◽  
Author(s):  
T J French ◽  
A W Goode ◽  
M J Holness ◽  
P A MacLennan ◽  
M C Sugden
Keyword(s):  
Fatty Acids ◽  
Pyruvate Dehydrogenase ◽  
Surgical Stress ◽  
Pyruvate Dehydrogenase Complex ◽  
Elevated Concentration ◽  
Fed State ◽  
Esterified Fatty Acids ◽  
The Relationship ◽  
Complex Activities ◽  
Dehydrogenase Complex

An elevated concentration of non-esterified fatty acids in the fed state elicited inhibition of cardiac, but not hepatic, pyruvate dehydrogenase complex (PDH). There was a modest decline in fructose 2,6-bisphosphate (Fru-2,6-P2) concentration in heart, and, to a lesser extent, in liver. Surgical stress decreased PDH activities and Fru-2,6-P2 concentrations in both heart and liver. Only the former response was abolished if postoperative lipolysis was inhibited. Surgery also decreased the [Fru-2,6-P2] in gastrocnemius: this response was abolished if lipolysis was inhibited.

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