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Loranne Agius - One of the best experts on this subject based on the ideXlab platform.
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Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, inhibits triacylglycerol depletion in hepatocytes and lipolysis in adipocytes
FEBS letters, 1997Co-Authors: T D Spurway, Christopher I. Pogson, H. Stanley A. Sherratt, Loranne AgiusAbstract:The effects of Etomoxir, an inhibitor of mitochondrial long-chain fatty acid oxidation, on triacylglycerol metabolism in rat hepatocytes and adipocytes were investigated. Etomoxir inhibited the depletion of triacylglycerol stores in hepatocytes incubated without exogenous fatty acids and inhibited lipolysis in adipocytes. The effects on hepatocytes could be attributed to two mechanisms. At low concentrations (1-10 microM) R-Etomoxir increased fatty acid esterification by inhibition of beta-oxidation. This effect was specific for the R-enantiomer and was associated with increased triacylglycerol secretion. At higher concentrations (50-100 microM) RS-Etomoxir inhibited lipolysis and triacylglycerol secretion, independently of inhibition of carnitine palmitoyl-transferase I. These effects of RS-Etomoxir on triacylglycerol metabolism and lipolysis may contribute to the chronic hypolipidaemic effects of Etomoxir in vivo.
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Differences between human, rat and guinea pig hepatocyte cultures. A comparative study of their rates of beta-oxidation and esterification of palmitate and their sensitivity to R-Etomoxir.
Biochemical pharmacology, 1991Co-Authors: Loranne Agius, Matthew Peak, H. Stanley A. SherrattAbstract:Rat hepatocyte cultures have higher rates of beta-oxidation of palmitate and lower rates of esterification to glycerolipid than human or guinea pig hepatocytes. The R-enantiomer of Etomoxir (sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), a hypoglycaemic compound and inhibitor of carnitine palmitoyltransferase I, inhibited palmitate beta-oxidation in all three species, but the sensitivity to inhibition was highest in human hepatocytes and lowest in rat hepatocytes. The concentration causing half-maximal inhibition was approximately: 0.1 microM in human; 1 microM in guinea pig and 10 microM in rat hepatocytes. In human and in guinea pig hepatocytes the inhibition of beta-oxidation by R-Etomoxir was associated with an increase in the esterification of palmitate but in rat hepatocytes R-Etomoxir lowered the total rate of palmitate metabolism. The S-enantiomer of Etomoxir had no significant effect on beta-oxidation or esterification of palmitate in any of the three species. It is concluded that there are significant differences between human, rat and guinea pig hepatocytes, not only in the relative partitioning of palmitate between beta-oxidation and esterification, but also in the sensitivity to an inhibitor of carnitine palmitoyltransferase I.
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Stereospecificity of the inhibition by Etomoxir of fatty acid and cholesterol synthesis in isolated rat hepatocytes.
Biochemical pharmacology, 1991Co-Authors: Loranne Agius, E. J. Meredith, H. S. A. SherrattAbstract:The racemates of substituted 2-oxiranecarboxylates are potent inhibitors of fatty acid oxidation and fatty acid and cholesterol synthesis. We show in the accompanying paper [Agius L, Peak M and Sherratt HSA, Biochem Pharmacol 42: 1711-1715, 1991] that only the R-enantiomer of Etomoxir, a potent hypoglycaemic compound, inhibits fatty acid oxidation in hepatocytes. We demonstrate in this paper that although the R-enantiomer of Etomoxir is esterified to its CoA-ester more readily than the S-enantiomer, both the R- and S-enantiomers are equally potent inhibitors of fatty acid and cholesterol synthesis from acetate in rat hepatocytes. The inhibition of fatty acid synthesis is not due to direct inhibition of fatty acid synthetase and the inhibition of cholesterol synthesis occurs at a site proximal to formation of mevalonate. Since the S-enantiomer inhibits fatty acid and cholesterol synthesis but not fatty acid oxidation the inhibition of the biosynthetic pathways is not coupled to inhibition of fatty acid oxidation.
Wolfgang Langhans - One of the best experts on this subject based on the ideXlab platform.
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augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Silvie Timmers, Wolfgang Langhans, Miranda Nabben, Ellen Lenaers, Gert Schaart, Madeleen Bosma, Bianca W J Van Bree, Denis Van Beurden, Margriet S Westerterpplantenga, Matthijs K. C. HesselinkAbstract:A low fat oxidative capacity has been linked to muscle diacylglycerol (DAG) accumulation and insulin resistance. Alternatively, a low fat oxidation rate may stimulate glucose oxidation, thereby enhancing glucose disposal. Here, we investigated whether an ethyl-2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylate (Etomoxir)-induced inhibition of fat oxidation leads to muscle fat storage and insulin resistance. An intervention in healthy male subjects was combined with studies in human primary myotubes. Furthermore, muscle DAG and triacylglycerol (TAG), mitochondrial function, and insulin signaling were examined in Etomoxir-treated C57bl6 mice. In humans, Etomoxir administration increased glucose oxidation at the expense of fat oxidation. This effect was accompanied by an increased abundance of GLUT4 at the sarcolemma and a lowering of plasma glucose levels, indicative of improved glucose homeostasis. In mice, Etomoxir injections resulted in accumulation of muscle TAG and DAG, yet improved insulin-stimulated GLUT4 translocation. Also in human myotubes, insulin signaling was improved by Etomoxir, in the presence of increased intramyocellular lipid accumulation. These insulin-sensitizing effects in mice and human myotubes were accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Our results show that a reduction in fat oxidation leading to accumulation of muscle DAG does not necessarily lead to insulin resistance, as the reduction in fat oxidation may activate AMPK.
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Etomoxir induced increase in ucp3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter
The FASEB Journal, 2002Co-Authors: Patrick Schrauwen, Vera Hinderling, Matthijs K. C. Hesselink, Gert Schaart, Margriet S Westerterpplantenga, Esther Kornips, Wim H M Saris, Wolfgang LanghansAbstract:The physiological function of human uncoupling protein-3 is still unknown. Uncoupling protein- 3 is increased during fasting and high-fat feeding. In these situations the availability of fatty acids to the mitochondria exceeds the capacity to metabolize fatty acids, suggesting a role for uncoupling protein-3 in handling of non-metabolizable fatty acids. To test the hypothesis that uncoupling protein-3 acts as a mitochondrial exporter of non-metabolizable fatty acids from the mitochondrial matrix, we gave human subjects Etomoxir (which blocks mitochondrial entry of fatty acids) or placebo in a cross-over design during a 36-h stay in a respiration chamber. Etomoxir inhibited 24-h fat oxidation and fat oxidation during exercise by ~14-19%. Surprisingly, uncoupling protein-3 content in human vastus lateralis muscle was markedly up- regulated within 36 h of Etomoxir administration. Up-regulation of uncoupling protein-3 was accompanied by lowered fasting blood glucose and increased translocation of glucose transporter-4. These data support the hypothesis that the physiological function of uncoupling protein-3 is to facilitate the outward transport of non-metabolizable fatty acids from the mitochondrial matrix and thus prevents mitochondria from the potential deleterious effects of high fatty acid levels. In addition our data show that up-regulation of uncoupling protein-3 can be beneficial in the treatment of type 2 diabetes.
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Etomoxir induced increase in ucp3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter
The FASEB Journal, 2002Co-Authors: Patrick Schrauwen, Vera Hinderling, Matthijs K. C. Hesselink, Gert Schaart, Margriet S Westerterpplantenga, Esther Kornips, Wim H M Saris, Wolfgang LanghansAbstract:The physiological function of human uncoupling protein-3 is still unknown. Uncoupling protein-3 is increased during fasting and high-fat feeding. In these situations the availability of fatty acids to the mitochondria exceeds the capacity to metabolize fatty acids, suggesting a role for uncoupling protein-3 in handling of non-metabolizable fatty acids. To test the hypothesis that uncoupling protein-3 acts as a mitochondrial exporter of non-metabolizable fatty acids from the mitochondrial matrix, we gave human subjects Etomoxir (which blocks mitochondrial entry of fatty acids) or placebo in a cross-over design during a 36-h stay in a respiration chamber. Etomoxir inhibited 24-h fat oxidation and fat oxidation during exercise by approximately 14-19%. Surprisingly, uncoupling protein-3 content in human vastus lateralis muscle was markedly up-regulated within 36 h of Etomoxir administration. Up-regulation of uncoupling protein-3 was accompanied by lowered fasting blood glucose and increased translocation of glucose transporter-4. These data support the hypothesis that the physiological function of uncoupling protein-3 is to facilitate the outward transport of non-metabolizable fatty acids from the mitochondrial matrix and thus prevents mitochondria from the potential deleterious effects of high fatty acid levels. In addition our data show that up-regulation of uncoupling protein-3 can be beneficial in the treatment of type 2 diabetes.
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The effect of Etomoxir on 24-h substrate oxidation and satiety in humans
The American journal of clinical nutrition, 2002Co-Authors: Vera Hinderling, Patrick Schrauwen, Wolfgang Langhans, Margriet S. Westerterp-plantengaAbstract:BACKGROUND: The carnitine O-palmitoyltransferase I (EC 2.3.1.21) inhibitor Etomoxir inhibits fatty acid oxidation, and hepatic fatty acid oxidation has been suggested to be a metabolic satiety signal in subjects who consume high-fat diets. OBJECTIVE: We investigated substrate oxidation and satiety after repeated administrations of Etomoxir or placebo in subjects who consumed a high-fat diet. DESIGN: In a randomized crossover design consisting of three 5-d treatments, we fed 10 healthy men [mean +/- SE age: 25.6 +/- 1.7 y; mean +/- SE body mass index (in kg/m(2)): 21.8 +/- 0.3] a high-fat diet twice and a low-fat diet once. The subjects consumed each diet at home for 3 consecutive days, after which they spent 36 h in energy balance in a respiration chamber. During the chamber stays with the high-fat treatments, Etomoxir or placebo was administered in 5 doses (600 mg Etomoxir in total). Blood samples were obtained on the mornings of days 4 and 5 of each treatment, and appetite profiles were assessed. RESULTS: Mean (+/-SE) 24-h respiratory quotients were significantly (P < 0.05) higher with repeated administrations of Etomoxir (0.833 +/- 0.004) than with repeated administrations of placebo (0.814 +/- 0.006), and mean (+/-SE) 24-h whole-body fat oxidation tended to be less (13.7%, P = 0.06) with administration of Etomoxir (136.0 +/- 5.2 g/d) than with administration of placebo (157.5 +/- 5.6 g/d). With the Etomoxir treatment, fat balance was positive (P < 0.0001) and carbohydrate balance was negative (P < 0.001), whereas with the placebo treatment, neither of the balances was significantly different from zero. Hunger and satiety ratings were not affected under these conditions. CONCLUSIONS: Etomoxir decreased whole-body fat oxidation, as indicated by the respiratory quotients in the healthy subjects. With the current protocol, however, hunger and satiety ratings were not affected.
T D Spurway - One of the best experts on this subject based on the ideXlab platform.
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The flux control coefficient of carnitine palmitoyltransferase I on palmitate beta-oxidation in rat hepatocyte cultures.
The Biochemical journal, 1997Co-Authors: T D Spurway, H A Sherratt, C I Pogson, L AgiusAbstract:Two important factors that determine the flux of hepatic beta-oxidation of long-chain fatty acids are the availability of fatty acid and the activity of carnitine palmitoyltransferase I (CPT I). Using Metabolic Control Analysis, the flux control coefficient of CPT I in rat hepatocyte monolayers was determined by titration with 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate (Etomoxir), which is converted to Etomoxir-CoA, an irreversible inhibitor of CPT I. We measured CPT I activity and flux through beta-oxidation at 0.2 mM and 1.0 mM palmitate to simulate substrate concentrations in fed and fasted states. Rates of beta-oxidation were 4.5-fold higher at 1. 0 mM palmitate compared with 0.2 mM palmitate. Flux control coefficients of CPT I, estimated by two independent methods, were similar: 0.67 and 0.79 for 0.2 mM palmitate, and 0.68 and 0.77 for 1 mM palmitate. It is concluded that the regulatory potential of CPT I is similar at low and high physiological concentrations of palmitate.
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Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, inhibits triacylglycerol depletion in hepatocytes and lipolysis in adipocytes
FEBS letters, 1997Co-Authors: T D Spurway, Christopher I. Pogson, H. Stanley A. Sherratt, Loranne AgiusAbstract:The effects of Etomoxir, an inhibitor of mitochondrial long-chain fatty acid oxidation, on triacylglycerol metabolism in rat hepatocytes and adipocytes were investigated. Etomoxir inhibited the depletion of triacylglycerol stores in hepatocytes incubated without exogenous fatty acids and inhibited lipolysis in adipocytes. The effects on hepatocytes could be attributed to two mechanisms. At low concentrations (1-10 microM) R-Etomoxir increased fatty acid esterification by inhibition of beta-oxidation. This effect was specific for the R-enantiomer and was associated with increased triacylglycerol secretion. At higher concentrations (50-100 microM) RS-Etomoxir inhibited lipolysis and triacylglycerol secretion, independently of inhibition of carnitine palmitoyl-transferase I. These effects of RS-Etomoxir on triacylglycerol metabolism and lipolysis may contribute to the chronic hypolipidaemic effects of Etomoxir in vivo.
Pang Zhang - One of the best experts on this subject based on the ideXlab platform.
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fatty acid degradation plays an essential role in proliferation of mouse female primordial germ cells via the p53 dependent cell cycle regulation
Cell Cycle, 2016Co-Authors: Hui Teng, Cong Shen, Cheng Zhou, Ye Yang, Pang ZhangAbstract:ABSTRACTPrimordial germ cells (PGCs) are embryonic founders of germ cells that ultimately differentiate into oocytes and spermatogonia. Embryonic proliferation of PGCs starting from E11.5 ensures the presence of germ cells in adulthood, especially in female mammals whose total number of oocytes declines after this initial proliferation period. To better understand mechanisms underlying PGC proliferation in female mice, we constructed a proteome profile of female mouse gonads at E11.5. Subsequent KEGG pathway analysis of the 3,662 proteins profiled showed significant enrichment of pathways involved in fatty acid degradation. Further, the number of PGCs found in in vitro cultured fetal gonads significantly decreased with application of Etomoxir, an inhibitor of the key rate-limiting enzyme of fatty acid degradation carnitine acyltransferase I (CPT1). Decrease in PGCs was further determined to be the result of reduced proliferation rather than apoptosis. The inhibition of fatty acid degradation by Etomoxir h...
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Fatty acid degradation plays an essential role in proliferation of mouse female primordial germ cells via the p53-dependent cell cycle regulation
2016Co-Authors: Hui Teng, Pang Zhang, Cong Shen, Cheng Zhou, Ye Yang, Xuesong Sui, Xuejiang Guo, Ran HuoAbstract:Primordial germ cells (PGCs) are embryonic founders of germ cells that ultimately differentiate into oocytes and spermatogonia. Embryonic proliferation of PGCs starting from E11.5 ensures the presence of germ cells in adulthood, especially in female mammals whose total number of oocytes declines after this initial proliferation period. To better understand mechanisms underlying PGC proliferation in female mice, we constructed a proteome profile of female mouse gonads at E11.5. Subsequent KEGG pathway analysis of the 3,662 proteins profiled showed significant enrichment of pathways involved in fatty acid degradation. Further, the number of PGCs found in in vitro cultured fetal gonads significantly decreased with application of Etomoxir, an inhibitor of the key rate-limiting enzyme of fatty acid degradation carnitine acyltransferase I (CPT1). Decrease in PGCs was further determined to be the result of reduced proliferation rather than apoptosis. The inhibition of fatty acid degradation by Etomoxir has the potential to activate the Ca2+/CamKII/5′-adenosine monophosphate-activated protein kinase (AMPK) pathway; while as an upstream activator, activated AMPK can function as activator of p53 to induce cell cycle arrest. Thus, we detected the expressional level of AMPK, phosphorylated AMPK (P-AMPK), phosphorylated p53 (P-p53) and cyclin-dependent kinase inhibitor 1 (p21) by Western blots, the results showed increased expression of them after treatment with Etomoxir, suggested the activation of p53 pathway was the reason for reduced proliferation of PGCs. Finally, the involvement of p53-dependent G1 cell cycle arrest in defective proliferation of PGCs was verified by rescue experiments. Our results demonstrate that fatty acid degradation plays an important role in proliferation of female PGCs via the p53-dependent cell cycle regulation.
M. Vázquez - One of the best experts on this subject based on the ideXlab platform.
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Uncoupling protein-3 mRNA up-regulation in C2C12 myotubes after Etomoxir treatment.
Biochimica et biophysica acta, 2001Co-Authors: Àgatha Cabrero, Marta Alegret, Rosa M. Sánchez, Tomás Adzet, Juan C. Laguna, M. VázquezAbstract:Abstract Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters that uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane. Treatment of C2C12 myotubes for 24 h with 40 μM Etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase I (CPT-I), up-regulated uncoupling protein 3 (UCP-3) mRNA levels (2-fold induction), whereas UCP-2 mRNA levels were not modified. Etomoxir treatment also caused a 2.5-fold induction in M-CPT-I (muscle-type CPT-I) mRNA levels. In contrast, other well-known peroxisome proliferator-activated receptor α (PPARα) target genes, such as acyl-CoA oxidase and medium-chain acyl-CoA dehydrogenase, were not affected, suggesting that this transcription factor was not involved in the effects of Etomoxir. Since it has been reported that CPT-I inhibition by Etomoxir leads to a further increase in ceramide synthesis, we test the possibility that ceramides were involved in the changes reported. Similarly to Etomoxir, addition of 20 μM C 2 -ceramide to C2C12 myotubes for 3, 6 and 9 h resulted in increased UCP-3 and M-CPT-I mRNA levels. These results indicate that the effects on UCP-3 mRNA levels could be mediated by increased ceramide synthesis.
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Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, up-regulates uncoupling protein-3 mRNA levels in primary culture of rat preadipocytes.
Biochemical and biophysical research communications, 1999Co-Authors: Àgatha Cabrero, Marta Alegret, Rosa M. Sánchez, Tomás Adzet, Juan C. Laguna, M. VázquezAbstract:Abstract Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters that uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane. Treatment of primary culture of rat preadipocytes for 24 h with 40 μM Etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase I (CPT-I), up-regulated UCP-3 mRNA levels (3.6-fold induction), whereas changes in UCP-2 mRNA levels were not significant. As a consequence of increased UCP-3 expression, a fall in the mitochondrial membrane potential was detected by flow cytometry. Etomoxir treatment modified neither L-CPT-I (liver-type) nor PPARα mRNA levels in preadipocytes. In contrast, mRNA expression of acyl-CoA oxidase (ACO), the rate-limiting enzyme of peroxisomal fatty acid β-oxidation, whose transcription is controlled by PPARα, was significantly induced (1.3-fold induction, P = 0.015). These findings suggest that the effects of Etomoxir were mediated by PPARα. Since it has been reported that the intracellular accumulation of lipids following the inhibition of CPT-I by Etomoxir leads to a PPARα-mediated metabolic response that increases the expression of genes involved in alternate fatty acid oxidation pathways, these results seem to implicate UCP-3 in this protective metabolic response. It remains to be studied whether reductions in the expression of UCP-3 could compromise this response, giving rise to lipotoxic effects on cells.