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Rolf K. Berge - One of the best experts on this subject based on the ideXlab platform.
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serum carnitine metabolites and incident type 2 diabetes mellitus in patients with suspected stable angina pectoris
The Journal of Clinical Endocrinology and Metabolism, 2018Co-Authors: Elin Strand, Rolf K. Berge, Eirik Wilberg Rebnord, Malin R Flygel, Vegard Lysne, Gard Frodahl Tveitevag Svingen, Grethe S Tell, Kjetil Loland, Asbjørn SvardalAbstract:Context Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse. Objective We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D. Design A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and Palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment. Results Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and Palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk. Conclusion Serum levels of TML, γ-butyrobetaine, and the long-chained Palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.
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associations between fatty acid oxidation hepatic mitochondrial function and plasma acylcarnitine levels in mice
Nutrition & Metabolism, 2018Co-Authors: Bodil Bjørndal, Eva Katrine Alterås, Carine Lindquist, Asbjørn Svardal, Jon Skorve, Rolf K. BergeAbstract:The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (w/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (n = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated Palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and Palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced. This study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels.
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Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice
BMC, 2018Co-Authors: Bodil Bjørndal, Eva Katrine Alterås, Carine Lindquist, Asbjørn Svardal, Jon Skorve, Rolf K. BergeAbstract:Abstract Background The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. Methods C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (w/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (n = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. Results The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated Palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and Palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced. Conclusion This study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels
Hany F Sobhi - One of the best experts on this subject based on the ideXlab platform.
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Loss of IntralipidH- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling
2016Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Martin Hersberger, Blair E Warren, Hany F Sobhi, Manoj G, Er S. Clanachan, Michael ZauggAbstract:Background: Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether IntralipidH and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury. Methods: Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. IntralipidH (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by Palmitoylcarnitine were obtained. Results: IntralipidH did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not IntralipidH produced protective ROS during reperfusion, which activated Akt. IntralipidH failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but Palmitoylcarnitine could not rescue protection and enhance postischemic functiona
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the mechanism of intralipid mediated cardioprotection complex iv inhibition by the active metabolite Palmitoylcarnitine generates reactive oxygen species and activates reperfusion injury salvage kinases
PLOS ONE, 2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Marcus C Schaub, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F SobhiAbstract:Background: IntralipidH administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood. Methods: Sprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of IntralipidH 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with IntralipidH. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of IntralipidH palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release. Results: IntralipidH enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentrationdependently inhibited complex IV. Only Palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine (1 mM), administered at reperfusion, also fully mimicked IntralipidH-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner. Conclusions: Our data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, IntralipidH. Protection is elicited by the fatty acid intermediate Palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.
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Mitochondrial fatty acid uptake and complex IV inhibition by Palmitoylcarnitine in early type-2 diabetic hearts.
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:Panel A: carnitine palmitoyltransferase 1 and 2 (CPT1 and CPT2, respectively) activity at the onset of reperfusion in healthy (h-IR/IL(3 min)) and early diabetic (ff-IR/IL(3 min) hearts treated with 1% Intralipid®. *, significantly different from healthy hearts. N = 10 hearts in each group. Panel B: concentration-dependent inhibition of complex IV by Palmitoylcarnitine (C16∶0c) in permeabilized cardiac fibers of healthy (reproduced from reference [19]) and fructose-fed (ff) rats. Complex IV inhibition is given as relative decrease in oxygen consumption. IC50, concentration of Palmitoylcarnitine that reduces the respiration rate by 50%. N = 5–6 hearts per group. Data are or mean ± SD (panels A) or mean ± SEM (panel B).
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Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:BackgroundInsulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury.MethodsEarly type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by Palmitoylcarnitine were obtained.ResultsIntralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but Palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3.ConclusionsEarly type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection.
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Mitochondrial respiration in saponin-skinned cardiac fibers harvested at the end of the ischemia-reperfusion protocols.
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:Mitochondrial respiration was measured in the presence of glucose-derived (pyruvate/malate) or fat-derived substrates (Palmitoylcarnitine/malate). The measured oxygen consumption (normalized to citrate synthase activity) is expressed as nmol O2 s−1/CS. Data are presented as mean (SD). *, significantly increased compared to all other groups;#, significantly increased compared to ff-IR/IL.ff-IR, hearts from fructose-fed rats exposed to ischemia-reperfusion (IR) without treatment (N = 10); ff-IR/SEV, hearts from fructose-fed rats exposed to IR with sevoflurane (2 vol.-%) conditioning (N = 10); ff-IR/IL, hearts from fructose-fed rats exposed to IR with Intralipid (1%) treatment at the onset of reperfusion (N = 6).
Phinghow Lou - One of the best experts on this subject based on the ideXlab platform.
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Loss of IntralipidH- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling
2016Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Martin Hersberger, Blair E Warren, Hany F Sobhi, Manoj G, Er S. Clanachan, Michael ZauggAbstract:Background: Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether IntralipidH and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury. Methods: Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. IntralipidH (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by Palmitoylcarnitine were obtained. Results: IntralipidH did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not IntralipidH produced protective ROS during reperfusion, which activated Akt. IntralipidH failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but Palmitoylcarnitine could not rescue protection and enhance postischemic functiona
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the mechanism of intralipid mediated cardioprotection complex iv inhibition by the active metabolite Palmitoylcarnitine generates reactive oxygen species and activates reperfusion injury salvage kinases
PLOS ONE, 2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Marcus C Schaub, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F SobhiAbstract:Background: IntralipidH administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood. Methods: Sprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of IntralipidH 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with IntralipidH. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of IntralipidH palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release. Results: IntralipidH enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentrationdependently inhibited complex IV. Only Palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine (1 mM), administered at reperfusion, also fully mimicked IntralipidH-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner. Conclusions: Our data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, IntralipidH. Protection is elicited by the fatty acid intermediate Palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.
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Mitochondrial fatty acid uptake and complex IV inhibition by Palmitoylcarnitine in early type-2 diabetic hearts.
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:Panel A: carnitine palmitoyltransferase 1 and 2 (CPT1 and CPT2, respectively) activity at the onset of reperfusion in healthy (h-IR/IL(3 min)) and early diabetic (ff-IR/IL(3 min) hearts treated with 1% Intralipid®. *, significantly different from healthy hearts. N = 10 hearts in each group. Panel B: concentration-dependent inhibition of complex IV by Palmitoylcarnitine (C16∶0c) in permeabilized cardiac fibers of healthy (reproduced from reference [19]) and fructose-fed (ff) rats. Complex IV inhibition is given as relative decrease in oxygen consumption. IC50, concentration of Palmitoylcarnitine that reduces the respiration rate by 50%. N = 5–6 hearts per group. Data are or mean ± SD (panels A) or mean ± SEM (panel B).
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Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:BackgroundInsulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury.MethodsEarly type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by Palmitoylcarnitine were obtained.ResultsIntralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but Palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3.ConclusionsEarly type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection.
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Mitochondrial respiration in saponin-skinned cardiac fibers harvested at the end of the ischemia-reperfusion protocols.
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:Mitochondrial respiration was measured in the presence of glucose-derived (pyruvate/malate) or fat-derived substrates (Palmitoylcarnitine/malate). The measured oxygen consumption (normalized to citrate synthase activity) is expressed as nmol O2 s−1/CS. Data are presented as mean (SD). *, significantly increased compared to all other groups;#, significantly increased compared to ff-IR/IL.ff-IR, hearts from fructose-fed rats exposed to ischemia-reperfusion (IR) without treatment (N = 10); ff-IR/SEV, hearts from fructose-fed rats exposed to IR with sevoflurane (2 vol.-%) conditioning (N = 10); ff-IR/IL, hearts from fructose-fed rats exposed to IR with Intralipid (1%) treatment at the onset of reperfusion (N = 6).
Asbjørn Svardal - One of the best experts on this subject based on the ideXlab platform.
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serum carnitine metabolites and incident type 2 diabetes mellitus in patients with suspected stable angina pectoris
The Journal of Clinical Endocrinology and Metabolism, 2018Co-Authors: Elin Strand, Rolf K. Berge, Eirik Wilberg Rebnord, Malin R Flygel, Vegard Lysne, Gard Frodahl Tveitevag Svingen, Grethe S Tell, Kjetil Loland, Asbjørn SvardalAbstract:Context Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse. Objective We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D. Design A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and Palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment. Results Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and Palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk. Conclusion Serum levels of TML, γ-butyrobetaine, and the long-chained Palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.
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associations between fatty acid oxidation hepatic mitochondrial function and plasma acylcarnitine levels in mice
Nutrition & Metabolism, 2018Co-Authors: Bodil Bjørndal, Eva Katrine Alterås, Carine Lindquist, Asbjørn Svardal, Jon Skorve, Rolf K. BergeAbstract:The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (w/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (n = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated Palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and Palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced. This study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels.
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Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice
BMC, 2018Co-Authors: Bodil Bjørndal, Eva Katrine Alterås, Carine Lindquist, Asbjørn Svardal, Jon Skorve, Rolf K. BergeAbstract:Abstract Background The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. Methods C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (w/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (n = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. Results The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated Palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and Palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced. Conclusion This study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels
Eliana Lucchinetti - One of the best experts on this subject based on the ideXlab platform.
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Loss of IntralipidH- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling
2016Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Martin Hersberger, Blair E Warren, Hany F Sobhi, Manoj G, Er S. Clanachan, Michael ZauggAbstract:Background: Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether IntralipidH and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury. Methods: Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. IntralipidH (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by Palmitoylcarnitine were obtained. Results: IntralipidH did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not IntralipidH produced protective ROS during reperfusion, which activated Akt. IntralipidH failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but Palmitoylcarnitine could not rescue protection and enhance postischemic functiona
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the mechanism of intralipid mediated cardioprotection complex iv inhibition by the active metabolite Palmitoylcarnitine generates reactive oxygen species and activates reperfusion injury salvage kinases
PLOS ONE, 2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Marcus C Schaub, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F SobhiAbstract:Background: IntralipidH administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood. Methods: Sprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of IntralipidH 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with IntralipidH. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of IntralipidH palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release. Results: IntralipidH enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentrationdependently inhibited complex IV. Only Palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine (1 mM), administered at reperfusion, also fully mimicked IntralipidH-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner. Conclusions: Our data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, IntralipidH. Protection is elicited by the fatty acid intermediate Palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.
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Mitochondrial fatty acid uptake and complex IV inhibition by Palmitoylcarnitine in early type-2 diabetic hearts.
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:Panel A: carnitine palmitoyltransferase 1 and 2 (CPT1 and CPT2, respectively) activity at the onset of reperfusion in healthy (h-IR/IL(3 min)) and early diabetic (ff-IR/IL(3 min) hearts treated with 1% Intralipid®. *, significantly different from healthy hearts. N = 10 hearts in each group. Panel B: concentration-dependent inhibition of complex IV by Palmitoylcarnitine (C16∶0c) in permeabilized cardiac fibers of healthy (reproduced from reference [19]) and fructose-fed (ff) rats. Complex IV inhibition is given as relative decrease in oxygen consumption. IC50, concentration of Palmitoylcarnitine that reduces the respiration rate by 50%. N = 5–6 hearts per group. Data are or mean ± SD (panels A) or mean ± SEM (panel B).
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Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:BackgroundInsulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury.MethodsEarly type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by Palmitoylcarnitine were obtained.ResultsIntralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but Palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3.ConclusionsEarly type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection.
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Mitochondrial respiration in saponin-skinned cardiac fibers harvested at the end of the ischemia-reperfusion protocols.
2014Co-Authors: Phinghow Lou, Eliana Lucchinetti, Liyan Zhang, Andreas Affolter, Manoj Gandhi, Martin Hersberger, Blair E Warren, Helene Lemieux, Hany F Sobhi, Alexander S. ClanachanAbstract:Mitochondrial respiration was measured in the presence of glucose-derived (pyruvate/malate) or fat-derived substrates (Palmitoylcarnitine/malate). The measured oxygen consumption (normalized to citrate synthase activity) is expressed as nmol O2 s−1/CS. Data are presented as mean (SD). *, significantly increased compared to all other groups;#, significantly increased compared to ff-IR/IL.ff-IR, hearts from fructose-fed rats exposed to ischemia-reperfusion (IR) without treatment (N = 10); ff-IR/SEV, hearts from fructose-fed rats exposed to IR with sevoflurane (2 vol.-%) conditioning (N = 10); ff-IR/IL, hearts from fructose-fed rats exposed to IR with Intralipid (1%) treatment at the onset of reperfusion (N = 6).
