Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation

Jeoung, Nam Ho; Wu, Qiang‐Sheng; Joshi, Mandar; Jaśkiewicz, Jerzy; Bock, Cheryl B.; DePaoli‐Roach, Anna A.; Harris, Robert A.

doi:10.1042/bj20060125

Cited by 127 publications

(168 citation statements)

References 42 publications

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“…Its importance in whole body energy homeostasis is underscored by the recent description of global PDK4-knockout mice, which have a range of metabolic defects during starvation including lower concentrations of blood glucose and gluconeogenic intermediates in liver and a faster rate of pyruvate oxidation in muscle (17). In this report, we demonstrate that selective overexpression of PDK4 in heart results in significant changes in energy metabolism, including increased cardiac fatty acid utilization and decreased carbohydrate consumption with a corresponding increase in pyruvate concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Zhao¹,

Jeoung²,

Burgess³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

108

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Kliewer SA. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 294: H936-H943, 2008. First published December 14, 2007 doi:10.1152/ajpheart.00870.2007.-The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway. fatty acid; hypertrophy; transgenic mice THERE IS A GROWING AWARENESS that systemic perturbations in energy metabolism such as those that occur in diabetes mellitus and other forms of metabolic disease contribute to cardiovascular disease (9). The healthy heart is a metabolic omnivore capable of switching between fatty acids and carbohydrates to match energy demands with dietary and physiological conditions (30, 31). Under conditions of pressure overload and cardiac hypertrophy, increased carbohydrate oxidation is part of the adaptive response to increased workload (21). However, in diabetes the metabolic flexibility of the heart is diminished, and it becomes more reliant on fatty acids for energy (10,21,30,31). This may contribute to functional derangements by causing oxidative stress and the accumulation of harmful lipid intermediates (10,21,30,31).In heart and other tissues, competition between fatty acids and carbohydrates occurs at the level of pyruvate dehydrogenase (PDH), which catalyzes the conversion of pyruvate to acetyl-CoA, thereby linking glycolysis to the Krebs cycle and ATP production. PDH is active when glucose oxidation prevails for the generation of energy and repressed when glucose is in short supply, such as during fasting (14). Regulation of PDH is accomplished by its interconversion between an active, nonphosphorylated form and an inactive, phosphorylated form. Phosphorylation and inactivation of PDH is mediated by a family of four PDH kinases (PDK1-4) (14, 29). Expression of one of these isozymes, PDK4, is rapidly and markedly induced in heart and other tissues in response to various metabolic stimuli, including fasting and a high-fat diet (28,33,34,36). Transcription ...

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Section: Discussionmentioning

confidence: 99%

“…One microgram of total or mitochondrial protein from hearts of PDK4 transgenic mice or control littermates was run on a 10% acrylamide/bis (37.5:1) gel. PDK4 protein was detected with a previously described rabbit anti-mouse PDK4 antibody (17).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Zhao¹,

Jeoung²,

Burgess³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

108

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“…There are several conditions that result in the short-term regulation of PDC activity (17-19). The longterm regulation of PDK that occurs in starvation (18,20) and diabetes involves an increase in the amount of PDK protein, which results in stable increases in PDK activity (21). An induction of PDK4 leads to decreased glucose oxidation, which results in hyperglycemia.…”

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confidence: 99%

The STAT5A-Mediated Induction of Pyruvate Dehydrogenase Kinase 4 Expression by Prolactin or Growth Hormone in Adipocytes

et al. 2007

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The purpose of this study was to determine whether pyruvate dehydrogenase kinase (PDK)4 was expressed in adipocytes and whether PDK4 expression was hormonally regulated in fat cells. Both Northern blot and Western blot analyses were conducted on samples isolated from 3T3-L1 adipocytes after various treatments with prolactin (PRL), growth hormone (GH), and/or insulin. Transfection of PDK4 promoter reporter constructs was performed. In addition, glucose uptake measurements were conducted. Our studies demonstrate that PRL and porcine GH can induce the expression of PDK4 in 3T3-L1 adipocytes. Our studies also show that insulin pretreatment can attenuate the ability of these hormones to induce PDK4 mRNA expression. In addition, we identified a hormone-responsive region in the murine PDK4 promoter and characterized a STAT5 binding site in this region that mediates the PRL (sheep) and GH (porcine) induction in PDK4 expression in 3T3-L1 adipocytes. PDK4 is a STAT5A target gene. PRL is a potent inducer of PDK4 protein levels, results in an inhibition of insulin-stimulated glucose transport in fat cells, and likely contributes to PRL-induced insulin resistance. Diabetes 56:1623-1629, 2007 I t is well known that growth hormone (GH) and prolactin (PRL) induce signaling via the JAK-STAT pathway. In particular, STAT5 proteins are potently activated by these hormones (rev. in 1). GH is known to have profound effects on lipid metabolism (rev. in 2). The effects of PRL have been well characterized in mammary tissues, yet there is also evidence demonstrating that this hormone can affect adipose tissue in mice and humans (3,4). Yet, few molecular targets for the STAT5-mediated actions of GH and PRL on adipocytes have been identified. Although multiple lines of recent evidence suggest that STAT5 proteins can modulate adipocyte function (5-11), very few studies have identified direct STAT5 target genes in adipocytes. We recently observed that the GH and PRL inhibition of fatty acid synthase (FAS) transcription was mediated by a STAT5A binding site in the rat FAS promoter (12). Hence, our current efforts have been to identify other genes associated with glucose or lipid metabolism that are directly modulated by STAT5 proteins in adipocytes. In this study, we present data demonstrating that pyruvate dehydrogenase kinase (PDK)4 is a STAT5A target gene.PDK is a family of kinases that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) (rev. in 13). There are four tissue-specific isoforms of PDK, PDK1-4, that have been identified in mammals, and each has different patterns of gene expression (14 -16). The specificity in distribution, expression, and activity of each PDK isoform contributes to the long-term regulation of PDC in a given tissue and thus, in part, regulates glucose metabolism. There are several conditions that result in the short-term regulation of PDC activity (17-19). The longterm regulation of PDK that occurs in starvation (18,20) and diabetes involves an increase in the amount of PDK protein, whi...

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“…A similar situation has been demonstrated in the case of pyruvate dehydrogenase kinase isozymes. It has been reported that isozyme 4 (PDHK-4) is decreased in muscle, during prolonged fasting (6). HPLC analysis of tear samples shown in Fig.…”

Section: Proteinsmentioning

confidence: 93%

Effect of Ramadan Fasting on Tear Proteins

Sariri

Varasteh

Sajedi

2010

Acta Med. (Hradec Kralove, Czech Repub.)

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Muslims abstain from eating, drinking and smoking from dawn to sunset during the holy month of Ramadan. Prolonged fasting is thought to be among risk factors for many diseases, e.g., cardiovascular, gastrointestinal and various infectious diseases. It could also play a part in several eye diseases, including dry eye syndrome, glaucoma, and cataract. Toxic and oxidative effects due to increased concentrations of some biochemicals as a result of reduction in tear volume thought to play an important role in damaging ocular tissue. Human tear is an important biological fluid similar to blood in many aspects. Tear film is composed of three basic layers i.e. lipid, aqueous and mucin. The tear film covering the ocular surface presents a mechanical and antimicrobial barrier, and endures an optical refractive surface. The aim of this study was to analyze and compare tear protein of volunteers during fasting. Using two reliable analytical methods, i.e. electrophoresis and high performance liquid chromatography (HPLC), we compared tear protein content of sixty volunteers (35 males and 25 females, 23–27 years old) during fasting in holly month of Ramadan (FAST: n=62) and one month before Ramadan (CTRL: n=60). The results showed that some identified tear proteins decreased during fasting. On the other hand, the activity of some enzymes such as lysozyme, lactoferrin and alpha amylase also decreased in fasting samples. Electrophoresis results showed that tear protein patterns in FAST (P<0.05) were different from those of CTRL. There were a few more protein peaks in the FAST group (P<0.005) than in CTRL.

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Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation

Cited by 127 publications

References 42 publications

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

The STAT5A-Mediated Induction of Pyruvate Dehydrogenase Kinase 4 Expression by Prolactin or Growth Hormone in Adipocytes

Effect of Ramadan Fasting on Tear Proteins

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