Dichloroacetate-lnduced Changes in Liver of Normal and Diabetic Rats

Anderson, James W.; Karounos, Dennis G.; Yoneyama, Tatsuo; Hollingsworth, J. Rogers

doi:10.3181/00379727-149-38905

Cited by 11 publications

(13 citation statements)

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“…Lactate, pyruvate, and alanine levels were also lower, consistent with substrate limitation for gluconeogenesis being responsible for the lower blood glucose levels. These findings are similar to our previous findings with PDK4 Ϫ/Ϫ mice fed chow diet (23) and to the findings with the PDK inhibitor dichloroacetate, which also reduces gluconeogenic substrates (7) and glucose in starved (7,37) and diabetic rats (2,24,35). It should be noted, however, that the effects of PDK4 deficiency on PDC activity were surprisingly subtle.…”

Section: Discussionsupporting

confidence: 80%

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Jeoung¹,

Harris²

2008

American Journal of Physiology-Endocrinology and Metabolism

139

126

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Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab 295: E46 -E54, 2008. First published April 22, 2008 doi:10.1152/ajpendo.00536.2007.-The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4 Ϫ/Ϫ mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4 Ϫ/Ϫ mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4 Ϫ/Ϫ mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4 Ϫ/Ϫ mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4 Ϫ/Ϫ mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4 Ϫ/Ϫ mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4 Ϫ/Ϫ mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4 Ϫ/Ϫ mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.pyruvate dehydrogenase kinase-4-knockout mice; diet-induced obesity; glucose oxidation; fatty acid oxidation; branched-chain amino acids THE PYRUVATE DEHYDROGENASE COMPLEX (PDC) is required for the oxidative disposal of dietary carbohydrate. Decarboxylation of pyruvate produces acetyl-CoA for oxidation by the citric acid cycle or conversion to fat. Since acetyl-CoA cannot be converted back to glucose, tight control of flux through PDC is required for maintenance of euglycemia during starvation. PDC activity has to be increased after meals but reduced during fasting. PDC activity is regulated by feedback inhibition by its products acetyl-CoA and NADH and by a balance between inactivation by pyruvate dehydrogenase kinases (PDKs) and activation by pyruvate dehydrogenase phosphatases (PDPs). In the well-fed state, PDC is relatively dephosphorylated and active for disposal of excess glucose. In the fasted state, PDC is highly phosphorylated and inactive so that three-carbon compounds can be converted back to glucose (50, 51). Four PDK isoenzymes (PDK1-4) and two PDP isoenzymes (PDP1 and -2) are expressed in mammalian tis...

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Section: Discussionsupporting

confidence: 80%

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Jeoung¹,

Harris²

2008

American Journal of Physiology-Endocrinology and Metabolism

139

126

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“…In ventricular myocytes, as in most mammalian cells, the intracellular environment is normally maintained in a reduced state due to a high GSH/GSSG ratio, which is controlled by the activities of two major enzymes: 1) GR, which catalyzes the reduction of GSSG to GSH using NADPH as a source of reducing equivalents; and 2) ␥-GCS, the rate-limiting step in GSH synthesis (5,22,31). It is also proposed that glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme of the pentose pathway, is the major source of NADPH utilized by GR (1,41). Under conditions of oxidative stress, GSH-mediated inactiva-tion of reactive oxygen species increases GSSG production, which decreases the GSH/GSSG ratio and leads to a more oxidized intracellular environment.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies from our laboratory have shown that I to density in isolated ventricular myocytes from rat hearts with chronic myocardial infarction (MI) is upregulated in vitro by compounds augmenting cellular levels of glutathione (30,38), an endogenous regulator of redox-sensitive cell functions (1,6,7,10,22). We have also reported that I to upregulation occurs in myocytes treated with metabolic agents that activate glucose utilization (29,39).…”

mentioning

confidence: 96%

Glutathione and K⁺ channel remodeling in postinfarction rat heart

Rozanski

Zhi

2002

American Journal of Physiology-Heart and Circulatory Physiology

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Electrical remodeling of the diseased ventricle is characterized by downregulation of K(+) channels that control action potential repolarization. Recent studies suggest that this shift in electrophysiological phenotype involves oxidative stress and changes in intracellular glutathione (GSH), a key regulator of redox-sensitive cell functions. This study examined the role of GSH in regulating K(+) currents in ventricular myocytes from rat hearts 8 wk after myocardial infarction (MI). Colorimetric analysis of tissue extracts showed that endogenous GSH levels were significantly less in post-MI hearts compared with controls, which is indicative of oxidative stress. This change in GSH status correlated with significant decreases in activities of glutathione reductase and gamma-glutamylcysteine synthetase. Voltage-clamp studies of isolated myocytes from post-MI hearts demonstrated that downregulation of the transient outward K(+) current (I(to)) could be reversed by pretreatment with exogenous GSH or N-acetylcysteine, a precursor of GSH. Upregulation of I(to) was also elicited by dichloroacetate, which increases glycolytic flux through the GSH-related pentose pathway. This metabolic effect was blocked by inhibitors of glutathione reductase and the pentose pathway. These data indicate that oxidative stress-induced alteration in the GSH redox state plays an important role in I(to) channel remodeling and that GSH homeostasis is influenced by pathways of glucose metabolism.

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“…DCA also exerts noteworthy effects on lipid and lipoprotein metabolism. In rats, the drug inhibits fatty acid and ketone body oxidation by peripheral tissues (13,14) and is reported either to inhibit (20) or to stimulate (21,22) fatty acid synthesis in liver without altering hepatocellular morphology (21,23). In addition, DCA reduces circulating triglyceride and cholesterol concentrations in obese (24) and diabetic (23,25) animals, but not in healthy animals (24,25).…”

Section: Introductionmentioning

confidence: 99%

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Stacpoole¹,

Harwood²,

Varnado³

1983

J. Clin. Invest.

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A B S T R A C T Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/ kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H20 incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (K; 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (K1 1.2 mM) and NADPH (K1 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (K, 5.6 mM Department of Medicine, College ylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.

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Dichloroacetate-lnduced Changes in Liver of Normal and Diabetic Rats

Cited by 11 publications

References 0 publications

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Glutathione and K⁺ channel remodeling in postinfarction rat heart

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

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Dichloroacetate-lnduced Changes in Liver of Normal and Diabetic Rats

Cited by 11 publications

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Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

Glutathione and K+ channel remodeling in postinfarction rat heart

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

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Glutathione and K⁺ channel remodeling in postinfarction rat heart