2006
DOI: 10.1016/j.cmet.2006.02.002
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Abstract: Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1al… Show more

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Cited by 3,086 publications
(2,512 citation statements)
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References 24 publications
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“…This is made possible through an increase in HIF-mediated expression of both glucose transporters and enzymes of the glycolytic pathway, giving tumours a "glycolytic" phenotype. Diversion of pyruvate toward lactate and away from OXPHOS is also promoted through increased HIF-mediated expression of two key enzymes; lactate dehydrogenase A (LDH-A) [26] and pyruvate dehydrogenase kinase 1 (PDK1) [27,28]. LDH-A is the enzyme responsible for conversion of pyruvate to lactate, and PDK1 is an inhibitor of pyruvate dehydrogenase that feeds pyruvate into the tricarboxylic acid cycle and thus toward OXPHOS.…”
Section: Metabolismmentioning
confidence: 99%
“…This is made possible through an increase in HIF-mediated expression of both glucose transporters and enzymes of the glycolytic pathway, giving tumours a "glycolytic" phenotype. Diversion of pyruvate toward lactate and away from OXPHOS is also promoted through increased HIF-mediated expression of two key enzymes; lactate dehydrogenase A (LDH-A) [26] and pyruvate dehydrogenase kinase 1 (PDK1) [27,28]. LDH-A is the enzyme responsible for conversion of pyruvate to lactate, and PDK1 is an inhibitor of pyruvate dehydrogenase that feeds pyruvate into the tricarboxylic acid cycle and thus toward OXPHOS.…”
Section: Metabolismmentioning
confidence: 99%
“…The molecular mechanisms of response to hypoxia are extremely complex, a key role being played by a transcriptional regulator, hypoxia-inducible factor (HIF), which orchestrates the expression of a wide variety of genes thought to be critical for adaptation to low oxygen. [15][16][17][18][19][20] While specific gene induction by low oxygen has arguably dominated hypoxia research, more recently the study of gene repression by hypoxia has received increasing attention. One of the interesting features of the latter process is its relative selectivity.…”
Section: Small Size Regulators With Far-reaching Impactmentioning
confidence: 99%
“…Accordingly, HIF activity plays a major role in chondrocyte metabolism and long bone growth In a series of recent studies, it was shown that while HIF promotes glycolysis, it also regulates energy generation at the mitochondrial level. HIF inhibits the activity of pyruvate dehydrogenase the enzyme which converts pyruvate into acetyl CoA, a critical substrate for enzymes of the TCA cycle [24]. Since the activity of this enzyme is carefully controlled by stimulatory (Ca 2+ , insulin etc) and inhibitory (phosphorylation) reactions, it is regarded as a rate-limiting enzyme.…”
Section: Regulation Of the Oxemic Response By Phd And Hif Proteinsmentioning
confidence: 99%