Studies of the long-term regulation of hepatic pyruvate dehydrogenase kinase

Sugden, Cameron; Fryer, G. D. Lee; Orfali, A. Karen; Priestman, Anne; Donald, Elaine; Holness, J. Mark

doi:10.1042/bj3290089

Cited by 41 publications

(43 citation statements)

References 29 publications

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“…In hypoinsulinaemic or insulin-resistant states this proportion is even higher, owing primarily to the chronic inhibition of PDH [73]. The latter is achieved acutely through the generation of mitochondrial acetyl-CoA as a product of fatty acid oxidation, and chronically through the fatty acid-mediated increase in the expression of PDH kinase [74,75]. Carnitine and its short-chain derivatives are able to overcome this inhibition, primarily by shifting the mitochondrial carnitine acetyltransferase-catalysed equilibrium away from acetyl-CoA and towards acetylcarnitine (see [76]).…”

Section: Cardiac Musclementioning

confidence: 99%

“…In Zucker fa\fa rats rats, β-cell GPAT expression is induced severalfold, and they accumulate TAG to a much greater extent than normal [133]. By analogy with other tissues, conditions characterized by increased circulating NEFA are also expected to result in the increased expression of PDH kinase [74,75], thus contributing to the impairment of the pathway leading from (glucose-derived) pyruvate to malonyl-CoA [134].…”

Section: Synthesis Of Glycerolipids In Muscle and Pancreatic β-Cellsmentioning

confidence: 99%

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The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Zammit

1999

Biochemical Journal

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Long-chain acyl-CoA esters have potent specific actions (e.g. on gene transcription, membrane trafficking) as well as non-specific ones (e.g. on phospholipid bilayers). They are synthesized on the cytosolic aspects of several intracellular membranes, to give rise to (a) cytosolic pool(s) to which a variety of enzymes and processes have access, including some localized in the nucleus. Their concentration in cells is highly regulated, interconversion with corresponding acylcarnitines being the most important mechanism involved. This reaction is catalysed by cytosol-accessible carnitine long-chain acyl (palmitoyl) transferase activities that are themselves located on multiple membrane systems. Regulation of these activities is through the inhibitory action of malonyl-CoA. Hence the existence of a potent malonyl-CoA-acyl-CoA axis through which many processes involved in the maintenance of mammalian cell function are regulated. The molecular, topographical and physiological interactions that make this possible are described and discussed.

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Section: Cardiac Musclementioning

confidence: 99%

Section: Synthesis Of Glycerolipids In Muscle and Pancreatic β-Cellsmentioning

confidence: 99%

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Zammit

1999

Biochemical Journal

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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).…”

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confidence: 99%

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Grassian¹,

Metallo²,

Coloff³

et al. 2011

Genes Dev.

172

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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“…Kinasecatalyzed inactivation of PDC plays a key role in limiting glucose oxidation when more abundant fatty acids are used to provide oxidative energy (2). This routinely occurs in many tissues but is particularly important during starvation (2,(13)(14)(15)(16)(17)(18), when limited glucose must be conserved for glucose-utilizing tissues such as brain. PDC is similarly down-regulated due to high PDK activity in the diabetic state (2,(15)(16)(17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Marked Differences between Two Isoforms of Human Pyruvate Dehydrogenase Kinase

Baker

Yan

Peng

et al. 2000

Journal of Biological Chemistry

112

194

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Pyruvate dehydrogenase kinase (PDK) isoforms 2 and 3 were produced via co-expression with the chaperonins GroEL and GroES and purified with high specific activities in affinity tag-free forms. By using human components, we have evaluated how binding to the lipoyl domains of the dihydrolipoyl acetyltransferase (E2) produces the predominant changes in the rates of phosphorylation of the pyruvate dehydrogenase (E1) component by PDK2 and PDK3. E2 assembles as a 60-mer via its C-terminal domain and has mobile connections to an E1-binding domain and then two lipoyl domains, L2 and L1 at the N terminus. PDK3 was activated 17-fold by E2; the majority of this activation was facilitated by the free L2 domain (half-maximal activation at 3.3 M L2). The direct activation of PDK3 by the L2 domain resulted in a 12.8-fold increase in k cat along with about a 2-fold decrease in the K m of PDK3 for E1. PDK3 was poorly inhibited by pyruvate or dichloroacetate (DCA). PDK3 activity was stimulated upon reductive acetylation of L1 and L2 when full activation of PDK3 by E2 was avoided (e.g. using free lipoyl domains or ADP-inhibited E2-activated PDK3). In marked contrast, PDK2 was not responsive to free lipoyl domains, but the E2-60-mer enhanced PDK2 activity by 10-fold. E2 activation of PDK2 resulted in a greatly enhanced sensitivity to inhibition by pyruvate or DCA; pyruvate was effective at significantly lower levels than DCA. E2-activated PDK2 activity was stimulated >3-fold by reductive acetylation of E2; stimulated PDK2 retained high sensitivity to inhibition by ADP and DCA. Thus, PDK3 is directly activated by the L2 domain, and fully activated PDK3 is relatively insensitive to feed-forward (pyruvate) and feed-back (acetylating) effectors. PDK2 was activated only by assembled E2, and this activated state beget high responsiveness to those effectors.

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Studies of the long-term regulation of hepatic pyruvate dehydrogenase kinase

Cited by 41 publications

References 29 publications

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Marked Differences between Two Isoforms of Human Pyruvate Dehydrogenase Kinase

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