Substituted 2-oxiranecarboxylic acids: a new group of candidate hypoglycaemic drugs

Selby, Peter; Sherratt, H. S. A.

doi:10.1016/0165-6147(89)90049-7

Cited by 55 publications

(42 citation statements)

References 20 publications

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“…4); we found that even in the presence of the lowest concentration of compound C (10 M), adipocytes elicited a 2.4-fold increase in palmitate oxidation reaching 3.7-fold increase in the presence of 40 M. (c) Compound C increased palmitate oxidation in the presence of malonyl-CoA and etomoxir (Fig. 6), two well known inhibitors of CPT1 activity (20,32). Compound C increased palmitate oxidation in cells exposed to malonyl-CoA by ϳ1.8-fold relative to control, and completely prevented the reduction in palmitate oxidation induced by etomoxir (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…Interestingly, incubation of isolated adipocytes with AICAR caused average reductions of 32 and 41% in palmitate and oleate uptake, respectively. Isolated adipocytes reduced by 20,30,40,30, and 40% palmitate and by 42, 55, 41, 41, and 28% oleate uptake after 1-5 min of exposure to these fatty acids, respectively (Fig. 5, A and B).…”

Section: Dose-response Effect Of Compound C On the Production Of 14 Cmentioning

confidence: 99%

“…Production of 14 (20). Importantly, intact cells are impermeable to malonyl-CoA; therefore, we used digitonin to permeabilize the adipocytes (21).…”

Section: Production Of 14 Co 2 From [1-14 C]palmitic Acid and [1-mentioning

confidence: 99%

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5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes

Gaidhu

Fediuc

Ceddia

2006

Journal of Biological Chemistry

103

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The objective of this study was to investigate the effects of 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR)-induced AMP-activated protein kinase (AMPK) activation on basal and insulin-stimulated glucose and fatty acid metabolism in isolated rat adipocytes. AICAR-induced AMPK activation profoundly inhibited basal and insulin-stimulated glucose uptake, lipogenesis, glucose oxidation, and lactate production in fat cells. We also describe the novel findings that AICAR-induced AMPK phosphorylation significantly reduced palmitate (32%) and oleate uptake (41%), which was followed by a 50% reduction in palmitate oxidation despite a marked increase in AMPK and acetyl-CoA carboxylase phosphorylation. Compound C, a selective inhibitor of AMPK, not only completely prevented the inhibitory effect of AICAR on palmitate oxidation but actually caused a 2.2-fold increase in this variable. Compound C also significantly increased palmitate oxidation in the presence of inhibitory concentrations of malonyl-CoA and etomoxir indicating an increase in CPT1 activity. In contrast to skeletal muscle in which AMPK stimulates fatty acid oxidation to provide ATP as a fuel, we propose that AMPK activation inhibits lipogenesis and fatty acid oxidation in adipocytes. Inhibition of lipogenesis would conserve ATP under conditions of cellular stress, although suppression of intra-adipocyte oxidation would spare fatty acids for exportation to other tissues where their utilization is crucial for energy production. Additionally, the stimulatory effect of compound C on long chain fatty acid oxidation provides a novel pharmacological approach to promote energy dissipation in adipocytes, which may be of therapeutic importance for obesity and type II diabetes.

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Section: Discussionmentioning

confidence: 92%

Section: Dose-response Effect Of Compound C On the Production Of 14 Cmentioning

confidence: 99%

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5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes

Gaidhu

Fediuc

Ceddia

2006

Journal of Biological Chemistry

103

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“…Carnitine palmitoyltransferase I (CPT1) is responsible for transferring fatty acyl groups to carnitine and is the rate-limiting step in carnitine-dependent β-oxidation in mitochondria [19][20][21] . To evaluate the potential role of CPT1 in C8 and C10 β-oxidation, the well-characterised CPT1 irreversible inhibitor etomoxir was used [22][23][24] . Through 11 dose-response experiments, [U- 13 C]palmitic (C16) acid, which is well-known to depend on CPT1 for mitochondrial β-oxidation, was used as a positive control to allow us to determine the maximal concentration (50 µM) of etomoxir that could be used to inhibit CPT1 without affecting cell viability (100µM etomoxir caused cell death as judged by trypan blue exclusion).…”

Section: C10 β-Oxidation Following Cpt1 Inhibitionmentioning

confidence: 99%

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

et al. 2017

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No. of tables: 1 2 SUMMARY Objective: The medium chain triglyceride ketogenic diet contains both octanoic (C8) and decanoic (C10) acids. The diet is an effective treatment for pharmacoresistant epilepsy. Whilst the exact mechanism for its efficacy is not known, it is emerging that C10, but not C8, interacts with targets that can explain anti-seizure effects, e.g. peroxisome proliferator-activated receptor-γ (PPARγ) (eliciting mitochondrial biogenesis and increased antioxidant status) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. For such effects to occur, significant concentrations of C10 are likely to be required in the brain. Methods:In order to investigate how this might occur, we measured the β-oxidation rate of 13 C-labelled C8 and C10 in neuronal SH-SY5Y cells using isotope-ratio mass spectrometry. The effects of carnitine palmitoyl transferase I (CPT1) inhibition, with the CPT1 inhibitor etomoxir, on C8 and C10 β-oxidation were also investigated.Results: Both fatty acids were catabolised, as judged by 13 CO2 release. However, C10 was β-oxidised at a significantly lower rate; 20% of C8. This difference was explained by a clear dependence of C10 on CPT1 activity, which is low in neurons, whereas 66% of C8 β-oxidation was independent of CPT1. In addition, C10 β-oxidation was decreased further in the presence of C8.Significance: It is concluded that, since CPT1 is poorly expressed in the brain, C10 is relatively spared from β-oxidation and can accumulate. This is further facilitated by the presence of C8 in the MCT ketogenic diet, which has a sparing effect upon C10 β-oxidation.

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“…The various carnitine acyl-transferases also show differential sensitivity to inhibition by etomoxir, which is an aryl-substituted 2-oxirane carboxylic derivative [15][16][17] (Figure 1). The pharmacological effects of etomoxir and its pharmacological analogue 2-tetradecylglycidic acid (TDGA) are due to the fact that they are specific inhibitors of CPT I, which is the rate-limiting enzyme Figure 1 Structures of decanoyl-CoA, malonyl-CoA and etomoxiryl-CoA of fatty acid oxidation in mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Inhibition by etomoxir of rat liver carnitine octanoyltransferase is produced through the co-ordinate interaction with two histidine residues

Morillas

Clotet

Rubı́

et al. 2000

Biochemical Journal

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Rat peroxisomal carnitine octanoyltransferase (COT), which facilitates the transport of medium-chain fatty acids through the peroxisomal membrane, is irreversibly inhibited by the hypoglycaemia-inducing drug etomoxir. To identify the molecular basis of this inhibition, cDNAs encoding full-length wild-type COT, two different variant point mutants and one variant double mutant from rat peroxisomal COT were expressed in Saccharomyces cere isiae, an organism devoid of endogenous COT activity. The recombinant mutated enzymes showed activity towards both carnitine and decanoyl-CoA in the same range as the wild type. Whereas the wild-type version expressed in yeast was inhibited by etomoxir in an identical manner to COT from rat liver peroxisomes, the activity of the enzyme containing the

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Substituted 2-oxiranecarboxylic acids: a new group of candidate hypoglycaemic drugs

Cited by 55 publications

References 20 publications

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

Inhibition by etomoxir of rat liver carnitine octanoyltransferase is produced through the co-ordinate interaction with two histidine residues

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