Substrate interactions in the short- and long-term regulation of renal glucose oxidation

Sugden, Mary C.; Holness, Mark J.; Donald, Elaine; Lall, Harjinder

doi:10.1016/s0026-0495(99)90169-5

Cited by 19 publications

(18 citation statements)

References 43 publications

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“…Although less dramatic, starvation also increases PDK2 gene expression in the liver and kidney (8,11,12). Conditions that affect expression of the other two known PDK isoforms, PDK1 and PDK3, have not been found.…”

Section: Discussionmentioning

confidence: 96%

“…This decrease in activity is attributable at least in part to increased PDK activity (4,5,7,8), which in turn is attributable to increased PDK4 expression in heart (9), skeletal muscle (10,11), liver, kidney, and lactating mammary gland (12). Starvation also increases the amount of PDK2 in liver and kidney (8,12,13). Insulin treatment and refeeding reverse the effect of diabetes and starvation, respectively, on PDK4 expression in skeletal muscle (10), heart (9), and liver (P.W., R.A.H., unpublished observations).…”

mentioning

confidence: 99%

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

et al. 2002

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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

et al. 2002

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“…This response to starvation appears to be specific for PDK4 with no change in protein expression of PDK2 (a lower-specific activity pyruvatesensitive isoform) (6). By contrast, PDK2 protein expression is upregulated by starvation both in the liver (7) and in the kidneys (8). This suggests that the responses of individual PDK isoforms to insulin deficiency are dictated by tissue type and presumably function.…”

mentioning

confidence: 98%

Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding.

Holness

Kraus²,

Harris³

et al. 2000

Diabetes

158

154

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In using Western blot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoforms PDK2 and PDK4, this study demonstrates selective PDK isoform switching in specific skeletal muscle types in response to high-fat feeding that is associated with altered regulation of PDK activity by pyruvate. The administration of a diet high in saturated fats led to stable (~2-fold) increases in PDK activities in both a typical slow-twitch (soleus [SOL]) muscle and a typical fast-twitch (anterior tibialis [AT]) muscle. Western blot analysis revealed that high-fat feeding significantly increased (~2-fold; P < 0.001) PDK4 protein expression in SOL, with a modest (1.3-fold) increase in PDK2 protein expression. The relative increase in PDK4 protein expression in SOL was associated with a 7.6-fold increase in the pyruvate concentration that was required to elicit a 50% active pyruvate dehydrogenase complex, which indicates a marked decrease in the sensitivity of PDK to inhibition by pyruvate. In AT muscle, high-fat feeding elicited comparable (1.5-to 1.7-fold) increases (P < 0.05) in PDK4 and PDK2 protein expression. Loss of sensitivity of PDK to inhibition by pyruvate was less marked. The data suggest that a positive correlation exists between increases in PDK4 expression and the propensity with which muscles use lipid-derived fuels as respiratory substrates rather than with the degree of insulin resistance induced in skeletal muscles by high-fat feeding. In conclusion, high-fat feeding leads to selective upregulation of PDK4 expression in slow-twitch muscle in response to high-fat feeding in vivo, which is associated with a pronounced loss of sensitivity of PDK activity to acute inhibition by pyruvate. Thus, increased PDK4 expression may underlie the stable modification of the regulatory characteristics of PDK observed in slowtwitch muscle in response to high-fat feeding. Diabetes 49:775-781, 2000

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“…PDK1 transcription is stimulated by low oxygen levels (Kim et al 2006;Papandreou et al 2006), and PDK4 expression can be induced by nutrient deprivation, high-fat diet, and diabetes (Roche and Hiromasa 2007). PDK2 levels are also increased under low-nutrient conditions (Sugden et al 1998(Sugden et al , 1999Wu et al 2000). Increased PDK expression under these conditions allows for preferential oxidation of fatty acids, and promotes the utilization of alternative carbon sources for gluconeogenesis (Roche and Hiromasa 2007).…”

mentioning

confidence: 99%

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Grassian¹,

Metallo²,

Coloff³

et al. 2011

Genes Dev.

171

137

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Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECMattached cells. Additionally, epidermal growth factor (EGF), a potent inducer of Erk, positively regulates PDH flux through decreased PDK4 expression. Furthermore, overexpression of PDK4 in ECM-detached cells suppresses the ErbB2-mediated rescue of ATP levels, and in attached cells, PDK4 overexpression decreases PDH flux, de novo lipogenesis, and cell proliferation. Mining of microarray data from human tumor data sets revealed that PDK4 mRNA is commonly down-regulated in tumors compared with their tissues of origin. These results identify a novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation.

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Substrate interactions in the short- and long-term regulation of renal glucose oxidation

Cited by 19 publications

References 43 publications

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

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

Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding.

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

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