Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart

Wu, Pengfei; Sato, Juichi; Zhao, Yu; Jaśkiewicz, Jerzy; Popov, M.; Harris, A. Robert

doi:10.1042/bj3290197

Cited by 301 publications

(290 citation statements)

References 32 publications

(78 reference statements)

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“…2005), which further suppresses glucose oxidation by decreasing PDH activity (Wu et al. 1998). PDH is an important metabolic control point where the competition between carbohydrates and fatty acids as metabolic substrates is rapidly regulated in the heart (Lopaschuk et al.…”

Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

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Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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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%

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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“…Both membrane glucose transporter type 4 and mitochondrial pyruvate oxidation are reduced, thereby decreasing glucose import and inhibiting glucose oxidation, respectively 9, 10. However, it is less well understood how diabetes mellitus affects glycolytic enzymes.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Humphries

Matsuzaki

Vadvalkar

et al. 2017

JAHA

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BackgroundThe healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Diabetes mellitus disrupts this metabolic flexibility and promotes cardiomyopathy through mechanisms that are not completely understood. Phosphofructokinase 2 (PFK‐2) is a primary regulator of cardiac glycolysis and substrate selection, yet its regulation under normal and pathological conditions is unknown. This study was undertaken to determine how changes in insulin signaling affect PFK‐2 content, activity, and cardiac metabolism.Methods and ResultsStreptozotocin‐induced diabetes mellitus, high‐fat diet feeding, and fasted mice were used to identify how decreased insulin signaling affects PFK‐2 and cardiac metabolism. Primary adult cardiomyocytes were used to define the mechanisms that regulate PFK‐2 degradation. Both type 1 diabetes mellitus and a high‐fat diet induced a significant decrease in cardiac PFK‐2 protein content without affecting its transcript levels. Overnight fasting also induced a decrease in PFK‐2, suggesting it is rapidly degraded in the absence of insulin signaling. An unbiased metabolomic study demonstrated that decreased PFK‐2 in fasted animals is accompanied by an increase in glycolytic intermediates upstream of phosphofructokianse‐1, whereas those downstream are diminished. Mechanistic studies using cardiomyocytes showed that, in the absence of insulin signaling, PFK‐2 is rapidly degraded via both proteasomal‐ and chaperone‐mediated autophagy.ConclusionsThe loss of PFK‐2 content as a result of reduced insulin signaling impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a pathological impairment in diabetes mellitus.

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Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart

Cited by 301 publications

References 32 publications

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

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

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

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