Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus

Ratheiser, Klaus; Schneeweiß, Bruno; Waldhäusl, W.; Fasching, Peter; Korn, A; Nowotny, Peter; Rohac, Madeleine; Wolf, H. P. O.

doi:10.1016/0026-0495(91)90214-h

Cited by 77 publications

(63 citation statements)

References 29 publications

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“…The fasting plasma glucose concentration was reduced in animals receiving etomoxir, which was consistent with diminished glucose production (Fig. 3C) via gluconeogenesis (23)(24)(25)(47)(48)(49)(50) because glycogenolysisis in rats is completely suppressed after an 18-h fast. Exogenous insulin infusion elicited a similar increase in plasma insulin levels in all of the groups, and plasma glucose concentrations were maintained at euglycemic levels.…”

Section: Resultssupporting

confidence: 71%

“…After conversion to its CoA ester, R-etomoxir covalently inhibits carnitine palmitoyltransferase (CPT)-1 and blocks the entry of fatty acids into mitochondria (21,22). The racemic mixture of R-and S-etomoxir has hypoglycemic effects in humans and animal models with diabetes and has been proposed as a potentially useful therapeutic agent (23)(24)(25). Because prolonged treatment with high doses of etomoxir promotes triglyceride accumulation within tissues (as determined by chemical analysis of biopsy samples [26]), a second objective of the present study was to determine what effect such treatment might have on both whole-body insulin sensitivity and IMCL in rats.…”

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confidence: 99%

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Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

et al. 2001

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Cross-sectional studies in human subjects have used 1 H magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (lowfat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle.

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Section: Resultssupporting

confidence: 71%

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confidence: 99%

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

et al. 2001

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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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“…Such discrepancies could be because during long-term treatment intrahepatic lipolysis would not be inhibited by acipimox. By contrast, 6-day treatment of patients with type 2 diabetes with etomoxir, an inhibitor of carnitine palmitoyltransferase I (CPT I) (the key regulatory enzyme of mitochondrial fatty acid oxidation), markedly decreased hepatic glucose production (9). However, such irreversible inhibitors of fatty acid oxidation had undesirable effects, such as cardiac hypertrophy and rise in plasma VLDL-TG and free fatty acids (10).…”

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confidence: 99%

Effects of Benfluorex on Fatty Acid and Glucose Metabolism in Isolated Rat Hepatocytes

et al. 2002

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The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced ␤-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD ؉ /NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 mol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.

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Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus

Cited by 77 publications

References 29 publications

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

Prolonged Inhibition of Muscle Carnitine Palmitoyltransferase-1 Promotes Intramyocellular Lipid Accumulation and Insulin Resistance in Rats

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

Effects of Benfluorex on Fatty Acid and Glucose Metabolism in Isolated Rat Hepatocytes

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