Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of peroxisome proliferator activated receptor gamma coactivator (PGC‐1α)

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.

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Adaptive Increase in Pyruvate Dehydrogenase Kinase 4 during Starvation Is Mediated by Peroxisome Proliferator-Activated Receptor α

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2001.5608 ◽

2001 ◽

Vol 287 (2) ◽

pp. 391-396 ◽

Cited By ~ 139

Author(s):

Pengfei Wu ◽

Jeffrey M. Peters ◽

Robert A. Harris

Keyword(s):

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pyruvate Dehydrogenase Kinase 4

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Hypoxic Exposure Increases Energy Expenditure by Increasing Carbohydrate Oxidation in Mice

BioMed Research International ◽

10.1155/2020/6159407 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yeram Park ◽

Deunsol Hwang ◽

Hun-Young Park ◽

Jisu Kim ◽

Kiwon Lim

Keyword(s):

Glucose Metabolism ◽

Energy Expenditure ◽

Pyruvate Dehydrogenase ◽

Hypoxic Condition ◽

Open Circuit ◽

Pyruvate Dehydrogenase Kinase ◽

Hypoxic Exposure ◽

Control Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Aims. Hypoxic exposure improves glucose metabolism. We investigated to validate the hypothesis that carbohydrate (CHO) oxidation could increase in mice exposed to severe hypoxic conditions. Methods. Seven-week-old male ICR mice (n=16) were randomly divided into two groups: the control group (CON) was kept in normoxic condition (fraction of inspired O2=21%) and the hypoxia group (HYP) was exposed to hypoxic condition (fraction of inspired O2=12%, ≈altitude of 4,300 m). The CON group was pair-fed with the HYP group. After 3 weeks of hypoxic exposure, we measured respiratory metabolism (energy expenditure and substrate utilization) at normoxic conditions for 24 hours using an open-circuit calorimetry system. In addition, we investigated changes in carbohydrate mechanism-related protein expression, including hexokinase 2 (HK2), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), and regulator of the genes involved in energy metabolism (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α) in soleus muscle. Results. Energy expenditure (EE) and CHO oxidation over 24 hours were higher in the HYP group by approximately 15% and 34% (p<0.001), respectively. Fat oxidation was approximately 29% lower in the HYP group than the CON group (p<0.01). Body weight gains were significantly lower in the HYP group than in the CON group (CON vs. HYP; 1.9±0.9 vs. −0.3±0.9; p<0.001). Hypoxic exposure for 3 weeks significantly reduced body fat by approximately 42% (p<0.001). PDH and PGC1α protein levels were significantly higher in the HYP group (p<0.05). Additionally, HK2 was approximately 21% higher in the HYP group. Conclusions. Hypoxic exposure might significantly enhance CHO oxidation by increasing the expression of PDH and HK2. This investigation can be useful for patients with impaired glucose metabolism, such as those with type 2 diabetes.

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Abstract 331: Recovery of Mitochondrial Bioenergetics after Hypoxia via Regulating Pyruvate Dehydrogenase Kinase and Adenosine Monophosphate-activated Kinase

Circulation Research ◽

10.1161/res.115.suppl_1.331 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Jessica M Toli ◽

Minzhen He ◽

Carolyn Suzuki ◽

Maha Abdellatif

Keyword(s):

Fatty Acid ◽

Oxidative Phosphorylation ◽

Cardiac Myocytes ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Neonatal Rat ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Mitochondrial Bioenergetics ◽

Peroxisome Proliferator Activated Receptor

Mitochondrial quality control is critical for the survival of cardiac myocytes during stress. The purpose of this study was to examine the effect of metabolic substrates and regulators of metabolism on mitochondrial bioenergetics, as an indicator of mitochondrial quality, and how these factors might influence the recovery of the cell’s bioenergetics after hypoxia/ischemia. By monitoring oxygen consumption rates (OCR), in real-time, in live neonatal rat myocytes and human cardiac myocyte-differentiated induced pluripotent stem cells, we found that both cell types can maintain basal OCR efficiently with any metabolic substrate; however, the neonatal cells require both glucose and fatty acid, while the human adult cells require fatty acid only, for mounting maximum reserve respiratory capacity (RRC). Our data also show that subjecting cardiac myocytes to hypoxia results in a reduction of the cells’ basal OCR and oxidative phosphorylation, and exhausts the RRC, which is accompanied by an increase in pyruvate dehydrogenase kinase (Pdk) 1 and 4. Except for normalization of Pdk1 levels, there was little or no recovery of these parameters after reoxygenation. We, thus, hypothesized, that inhibition of Pdks may help recovery of the cell’s bioenergetics. Indeed, our results show that by inhibiting Pdks with dichloroacetate (DCA) before or after hypoxia, the cells’ bioenergetics, including OCR, oxidative phosphorylation, and RRC in neonatal myocytes, and RRC in the human myocytes fully recover within 24 h. On the other hand, activating AMP-activated kinase (AMPK) resulted in delayed (96 h) improvement of the cells’ RRC that was accompanied by an increase in peroxisome proliferator-activated receptor gamma, coactivator 1α (3.5x), peroxisome proliferator-activated receptor-α (2x), and mitochondrial number (2x). These results led us to conclude that compromised mitochondrial quality can be rescued through mechanisms that regulate glucose or fatty acid oxidation by either inhibiting Pdks or activating AMPK, respectively, in rodent and human myocytes.

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