Regulation of Pyruvate Dehydrogenase Kinase Expression by Peroxisome Proliferator–Activated Receptor-α Ligands, Glucocorticoids, and Insulin

Huang, Boli; Wu, Pengfei; Bowker-Kinley, Melissa M.; Harris, Robert A.

doi:10.2337/diabetes.51.2.276

Cited by 235 publications

(246 citation statements)

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“…The half-life of the PDK4 mRNA in Morris hepatoma cells is relatively short (ϳ1.5 h) compared with that of PDK2 (t1 ⁄2 Ͼ 6 h) (19). Increases in PDK2 mRNA and protein expression evoked by prolonged starvation on PDK isoform expression in liver and kidney are relatively similar (ϳ2-fold) in magnitude, suggesting that regulation of PDK2 expression occurs primarily at the level of transcription (65).…”

Section: Long-term Regulation Of Mammalian Pdk Expressionmentioning

confidence: 77%

“…Furthermore, the upregulation of hepatic and renal PDK4 protein expression normally evoked in response to prolonged starvation is markedly impaired in PPAR␣-deficient mice (49,50,67). Incubation of Morris hepatoma 7800C1 cells with WY-14643 or an FA (palmitate or oleate) increases PDK4 mRNA and protein (19). Thus there is compelling evidence that FAs, acting at least in part via PPAR␣, are important factors in the regulation of hepatic and renal PDK4 expression.…”

Section: Regulation Of Mammalian Pdk4 Expression By Pparsmentioning

confidence: 96%

“…This is demonstrated by greatly retarded reactivation of PDC in heart, which expresses PDK1, PDK2, and PDK4, compared with that in liver, which expresses only PDK2 and PDK4 (15,52). Insulin suppresses hepatoma PDK2 mRNA expression but is less effective at lowering hepatoma PDK4 mRNA expression (19). Differential sensitivity of PDK2 and PDK4 to suppression by insulin may possibly be extrapolated to other tissues.…”

Section: Long-term Regulation Of Mammalian Pdk Expressionmentioning

confidence: 99%

“…PPAR␣-deficient mice exhibit an impaired ability to upregulate hepatic FA oxidation in response to fasting, despite suppression of insulin levels and increases in FA supply (24,30). Activation of PPAR␣ by WY-14643 in vivo enhances hepatic and renal PDK4 protein expression in the fed state (19,51). Furthermore, the upregulation of hepatic and renal PDK4 protein expression normally evoked in response to prolonged starvation is markedly impaired in PPAR␣-deficient mice (49,50,67).…”

Section: Regulation Of Mammalian Pdk4 Expression By Pparsmentioning

confidence: 99%

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Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs

Sugden

Holness

2003

American Journal of Physiology-Endocrinology and Metabolism

456

416

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The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid (FA) synthesis. Knowledge of the mechanisms that regulate PDC activity is important, because PDC inactivation is crucial for glucose conservation when glucose is scarce, whereas adequate PDC activity is required to allow both ATP and FA production from glucose. The mechanisms that control mammalian PDC activity include its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDKs 1–4) and its dephosphorylation (activation, reactivation) by the pyruvate dehydrogenase phosphate phosphatases (PDPs 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states. In this review, we summarize recent significant advances in our knowledge of the mechanisms regulating PDC with emphasis on the PDKs, in particular PDK4, whose expression is linked with sustained changes in tissue lipid handling and which may represent an attractive target for pharmacological interventions aimed at modulating whole body glucose, lipid, and lactate homeostasis in disease states.

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Section: Long-term Regulation Of Mammalian Pdk Expressionmentioning

confidence: 77%

Section: Regulation Of Mammalian Pdk4 Expression By Pparsmentioning

confidence: 96%

Section: Long-term Regulation Of Mammalian Pdk Expressionmentioning

confidence: 99%

Section: Regulation Of Mammalian Pdk4 Expression By Pparsmentioning

confidence: 99%

See 2 more Smart Citations

Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs

Sugden

Holness

2003

American Journal of Physiology-Endocrinology and Metabolism

456

416

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“…Transcription of PDK4 is stimulated in heart and other tissues by the nuclear fatty acid receptor PPAR-␣ (15,28,34). Two recent studies showed that increased PPAR-␣ activity in heart can cause cardiomyopathy (11,37).…”

Section: Discussionmentioning

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

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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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Mechanistic population modeling of diabetes disease progression in Goto‐Kakizaki rat muscle

Nie

DuBois

Jusko

et al. 2010

Biopharm & Drug Disp

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Pyruvate dehydrogenase kinase 4 (PDK4) is a lipid status responsive gene involved in muscle fuel selection. Evidence is mounting in support of the therapeutic potential of PDK4 inhibitors to treat diabetes. Factors that regulate PDK4 mRNA expression include plasma corticosterone, insulin and free fatty acids. Our objective was to determine the impact of those plasma factors on PDK4 mRNA and to develop and validate a population mathematical model to differentiate aging, diet and disease effects on muscle PDK4 expression. The Goto-Kakizaki (GK) rat, a polygenic non-obese model of type 2 diabetes, was used as the diabetic animal model. We examined muscle PDK4 mRNA expression by real-time QRTPCR. Groups of GK rats along with controls fed with either a normal or high fat diet were sacrificed at 4, 8, 12, 16, and 20 weeks of age. Plasma corticosterone, insulin and free fatty acid were measured. The proposed mechanism-based model successfully described the age, disease and diet effects and the relative contribution of these plasma regulators on PDK4 mRNA expression. Muscle growth reduced the PDK4 mRNA production rate by 14% per gram increase. High fat diet increased the initial production rate constant in GK rats by 2.19-fold. The model indicated that corticosterone had a moderate effect and PDK4 was more sensitive to free fatty acid than insulin fluxes, which was in good agreement with the literature data.

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Regulation of Pyruvate Dehydrogenase Kinase Expression by Peroxisome Proliferator–Activated Receptor-α Ligands, Glucocorticoids, and Insulin

Cited by 235 publications

References 36 publications

Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs

Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs

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

Mechanistic population modeling of diabetes disease progression in Goto‐Kakizaki rat muscle

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