scholarly journals PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages

2016 ◽  
Vol 37 (1) ◽  
Author(s):  
Annemarie Guentsch ◽  
Angelika Beneke ◽  
Lija Swain ◽  
Katja Farhat ◽  
Shunmugam Nagarajan ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Phenotype ◽  
Protein Levels ◽  
Dehydrogenase Enzyme ◽  
Pyruvate Dehydrogenase Kinase 1 ◽  
And Function

ABSTRACT The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1α (HIF-1α) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macrophage behavior.

scholarly journals Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1

2007 ◽  
Vol 27 (21) ◽  
pp. 7381-7393 ◽  
Author(s):  
Jung-whan Kim ◽  
Ping Gao ◽  
Yen-Chun Liu ◽  
Gregg L. Semenza ◽  
Chi V. Dang
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Pyruvate Dehydrogenase ◽  
Hypoxia Inducible Factor ◽  
Pyruvate Dehydrogenase Kinase ◽  
Vascular Endothelial ◽  
Hexokinase 2 ◽  
Pyruvate Dehydrogenase Kinase 1 ◽  
Cell Growth And Proliferation ◽  
Endothelial Growth Factor

ABSTRACT Hypoxia is a pervasive microenvironmental factor that affects normal development as well as tumor progression. In most normal cells, hypoxia stabilizes hypoxia-inducible transcription factors (HIFs), particularly HIF-1, which activates genes involved in anaerobic metabolism and angiogenesis. As hypoxia signals a cellular deprivation state, HIF-1 has also been reported to counter the activity of MYC, which encodes a transcription factor that drives cell growth and proliferation. Since many human cancers express dysregulated MYC, we sought to determine whether HIF-1 would in fact collaborate with dysregulated MYC rather countering its function. Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. We also found the collaborative induction of vascular endothelial growth factor (VEGF) by HIF-1 and dysregulated c-Myc. This study reports the previously unsuspected collaboration between HIF-1 and dysregulated MYC and thereby provides additional insights into the regulation of VEGF and the Warburg effect, which describes the propensity for cancer cells to convert glucose to lactate.

scholarly journals Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1α

2021 ◽  
Vol 22 (16) ◽  
pp. 8610
Author(s):  
Nives Škorja Milić ◽  
Klemen Dolinar ◽  
Katarina Miš ◽  
Urška Matkovič ◽  
Maruša Bizjak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Hypoxia Inducible Factor ◽  
Muscle Cells ◽  
Pyruvate Dehydrogenase Kinase ◽  
Skeletal Muscle Cells ◽  
Dependent Manner ◽  
Protein Levels ◽  
L6 Myotubes

Inhibition of pyruvate dehydrogenase kinase (PDK) emerged as a potential strategy for treatment of cancer and metabolic disorders. Dichloroacetate (DCA), a prototypical PDK inhibitor, reduces the abundance of some PDK isoenzymes. However, the underlying mechanisms are not fully characterized and may differ across cell types. We determined that DCA reduced the abundance of PDK1 in breast (MDA-MB-231) and prostate (PC-3) cancer cells, while it suppressed both PDK1 and PDK2 in skeletal muscle cells (L6 myotubes). The DCA-induced PDK1 suppression was partially dependent on hypoxia-inducible factor-1α (HIF-1α), a transcriptional regulator of PDK1, in cancer cells but not in L6 myotubes. However, the DCA-induced alterations in the mRNA and the protein levels of PDK1 and/or PDK2 did not always occur in parallel, implicating a role for post-transcriptional mechanisms. DCA did not inhibit the mTOR signaling, while inhibitors of the proteasome or gene silencing of mitochondrial proteases CLPP and AFG3L2 did not prevent the DCA-induced reduction of the PDK1 protein levels. Collectively, our results suggest that DCA reduces the abundance of PDK in an isoform-dependent manner via transcriptional and post-transcriptional mechanisms. Differential response of PDK isoenzymes to DCA might be important for its pharmacological effects in different types of cells.

scholarly journals Myocardial remodeling in rats with metabolic syndrome: role of Rho-kinase mediated insulin resistance.

2012 ◽  
Vol 59 (2) ◽  
Author(s):  
Chuan-Bao Li ◽  
Xiao-Xing Li ◽  
Yu-Guo Chen ◽  
Hai-Qing Gao ◽  
Cheng-Mei Bao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Critical Role ◽  
Rho Kinase ◽  
Myocardial Damage ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Protein Levels ◽  
Transmission Electron ◽  
And Function

Insulin resistance (IR) plays a critical role in metabolic syndrome (MS). Previous studies have demonstrated that activated ROCK is increased in MS patients. However, the effect of Rho-kinase (ROCK) on IR has not been definitely determined. Thus, the aims of the present study were to determine whether ROCK activation induces IR or affects myocardial structure and function, as well as the possible mechanisms underlying this process. Wistar rats fed high fat, high glucose and high salt diet sewed as model of MS and we used transmission electron microscopy, echocardiogram technology, and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify any myocardial damage. The protein levels of MYPT-1 (characteristic of ROCK activation), IRS-1 and AKT were analyzed by immunohistochemistry and Western blotting. In hearts from MS rats, we found increased protein levels of phospho-MYPT-1 and phospho-IRS-1 (Ser307) and decreased phospho-AKT compared to levels in normal rats. In conclusion, the results suggest that ROCK-mediated IR is involved in the development of myocardial impairments in MS rats and that this effect is mediated probably via the IRS-1/PI3-kinase/AKT pathway.

ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4

2013 ◽  
Vol 304 (8) ◽  
pp. H1103-H1113 ◽  
Author(s):  
Jun Mori ◽  
Osama Abo Alrob ◽  
Cory S. Wagg ◽  
Robert A. Harris ◽  
Gary D. Lopaschuk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Critical Role ◽  
Pyruvate Dehydrogenase Kinase ◽  
Ang Ii ◽  
Oxidation Rates

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.

scholarly journals Pyruvate dehydrogenase kinase 1 and 2 deficiency reduces high-fat diet-induced hypertrophic obesity and inhibits the differentiation of preadipocytes into mature adipocytes

2021 ◽  
Author(s):  
Hyeon-Ji Kang ◽  
Byong-Keol Min ◽  
Won-Il Choi ◽  
Jae-Han Jeon ◽  
Dong Wook Kim ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Human Adipose Tissue ◽  
Pyruvate Dehydrogenase Kinase ◽  
Loss Of Function ◽  
High Fat

AbstractObesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity.

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