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Impact d'une inhibition de l'acétyl-CoA carboxylase sur les fonctions plaquettaires
Authors: --- ---
Year: 2017 Publisher: Bruxelles: UCL. Faculté de pharmacie et des sciences biomédicales,

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Introduction. Les plaquettes contrôlent l'hémostase en adhérant à l'endothélium en cas de lésion et en s'agrégeant. Les mécanismes mis en œuvre dans ce processus physiologique sont similaires à ceux responsables de la thrombose artérielle, une complication grave de l'athérosclérose qui peut mener à un infarctus du myocarde potentiellement mortel. Des données obtenues au laboratoire ont montré qu'une phosphorylation élevée et soutenue de l'acétyl-CoA carboxylase (ACC) est observée dans les plaquettes de patients souffrant d'une maladie coronaire athéromateuse. L'isoforme ACC1, majoritaire dans les plaquettes, est une enzyme clé de la lipogenèse qui peut être régulée par des modifications post­ traductionnelles. Sa phosphorylation inhibe son activité. Hypothèse. Étant donné l'importance du rôle joué par de nombreux lipides dans les plaquettes tant au niveau de substrats énergétiques que de molécules de signalisation, nous postulons qu'une modulation de la phosphorylation/activité de l'ACC pourrait altérer les fonctions plaquettaires (adhésion, activation, agrégation, rétraction du clou plaquettaire et activité pro-coagulante) et/ou le métabolisme énergétique, et par conséquent affecter la formation ou la stabilité d'un thrombus. Méthodes. Dans ce travail, nous avons utilisé un inhibiteur pharmacologique de l'ACC, le TOFA. Des plaquettes humaines ont été pré-incubées en présence de TOFA 30µM pendant 2 heures puis stimulées avec de la thrombine. Nous avons mesuré la lipogenèse via l'incorporation de 14C-acide acétique dans les lipides. Les fonctions plaquettaires ont été mesurées par agrégométrie, cytométrie de flux et microscopie. L'expression et la phosphorylation de certains médiateurs de signalisation ont été examinées par western blot. Le métabolisme des plaquettes a été évalué via la mesure de la consommation d'oxygène. Résultats. Nos résultats montrent que le TOFA diminue la lipogenèse dans les plaquettes. Cette diminution est associée à une altération de la morphologie, à une inhibition de la sécrétion des granules denses et de l'agrégation plaquettaire induites par la thrombine tandis que l'activation du récepteur a.IIbJ33 et la sécrétion des granules a ne sont pas affectés, suggérant que le défaut d'agrégation provient d'une diminution des effets autocrines et paracrines de l'ADP et de l'ATP. Nous montrons que les mécanismes impliqués dans la diminution de la sécrétion des granules denses font intervenir les PKC, notamment la PKCδ, et leurs substrats, la cytohésine-2 et la PKD. De plus, nos résultats suggèrent qu'une diminution du contenu en phosphatidylsérine pourrait contribuer, en partie, à l'inhibition des PKC. À côté de son impact majeur sur la signalisation des plaquettes, le TOFA affecte aussi leur métabolisme énergétique en diminuant la capacité de réserve respiratoire et la respiration mitochondriale liée à la production d'ATP. Conclusion. Notre étude démontre qu’une inhibition soutenue de l’ACC diminue la lipogenèse et affecte la sécrétion des granules denses et l’agrégation via un ou plusieurs mécanismes dépendant des PKC et du métabolisme énergétique. Nous pensons que cela pourrait affecter la stabilité du thrombus chez les patients athéromateux. Introduction: Platelets adhere to the endothelium of vessels when there is a breach and lead to the formation of a clot. By this phenomenon, platelets control hemostasis. Mechanisms involved in this physiological process are similar to those responsible for arterial thrombosis that is a severe complication of atherosclerosis. This disease can lead to myocardial infarction and death. Acetyl-CoA carboxylase (ACC) regulates fatty acids synthesis and oxidation. Previous results from the lab showed that ACC is phosphorylated in platelets from patients with coronary artery disease, potentially due to persistent thrombin generation. ACC phosphorylation results in its inhibition. Aims: Given the primary roles of lipids in platelets structure, energy storage and signaling, we hypothesized that a sustained inhibition of ACC could have consequences on platelets activation and bioenergetics. Methods: To test our hypothesis, platelets were treated with 30µM TOFA, an ACC inhibitor, for 2 hours before thrombin stimulation. We measured lipogenesis via l4C-acetate incorporation into fatty acids. Platelet functions were assessed by aggregometry and flow cytometric studies. Signaling mediators were evaluated by western blot and platelet mitochondrial function was reflected by the oxygen consumption rate. Results: We show that a pre incubation of platelets with TOFA significantly decreased lipogenesis (Control: 6 pmol/min/10 9 platelets ± 0.8; TOFA: 1 pmol/min/10 9 platelets ± 0.3; P<0.05). This effect was accompanied by a significant defect in dense granules secretion and aggregation in response to Iow thrombin concentrations, whereas u-granules secretion was not affected, suggesting that the default in aggregation likely resulted from a lower autocrine and paracrine role of ADP. PKC activity is essential for granule secretion. Accordingly, we show that TOFA significantly decreased PKC substrates phosphorylation in baseline and after thrombin stimulation. Since PKCδ has been shown to play a role in dense granules regulation, the effects of TOFA on its activity was evaluated through the analysis of VASP phosphorylation. Indeed, inhibition of PKCδ has been shown to promote hyper phosphorylation of its Serl57 in platelets. Treatment with TOFA led to a drastic increase of Serl57 phosphorylation, in baseline and after thrombin stimulation, and in a cAMP-independent way. In addition, TOFA treatment significantly decreased phosphorylation of cytohesin-2 and PKD, two PKC substrates playing a critical role in dense granules secretion. Platelet metabolism was also affected by a sustained ACC inhibition, as shown by the TOFA-induced decrease in reserve capacity and ATP-linked respiration. Conclusion: Our study shows that a sustained inhibition of platelet ACC decreases lipogenesis and affects (i) dense granule secretion and aggregation through a PKC/ PKCδ - dependent mechanism, and (ii) platelet bioenergetics. We believe that it could affect thrombus stabilization in atherosclerotic patients.


Book
Comparaison des effets de la glutamine sur l'activité de l'acétyl-CoA carboxylase et de l'hydroxyméthylglutaryl-CoA réductase dans des hépatocytes isolés
Authors: --- ---
Year: 1996 Publisher: Bruxelles: UCL,

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La synthèse de glycogène et la lipogenèse sont stimulées par le gonflement cellulaire induit pas la glutamine. Ceci suggère que le gonflement pourrait jouer un rôle anabolique général et s’appliquer à d’autres voies anaboliques telle que la synthèse de cholestérol. Cette hypothèque est renforcée par le fait que l’enzyme-clé de cette voie métabolique, l’HMG-CoA réductase, est comme l’ACC activée par une protéine phosphatase de type-2A et inactivée par l’AMP-PK. Dès lors, par analogie avec l’ACC, l’HMG-CoA réductase pourrait être un substrat pour la GAPP et donc être activée par incubation des hépatocytes en présence de glutamine. Cette hypothèse a été testée au cours de ce mémoire


Dissertation
Molecular genetic studies on peroxisomal 3-oxoacyl-CoA thiolase
Authors: ---
Year: 1991 Publisher: Amsterdam Rodopi

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Book
Die aktivierte Essigsäure : das Coenzym A und seine Acylderivate im Stoffwechsel der Zelle
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Year: 1959 Publisher: Stuttgart : Enke,

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Dissertation
Transcriptional regulation of genes encoding proteins involved in peroxisome biogenesis in yeast
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Year: 1992 Publisher: Enschede Febo


Book
AMP-Activated Protein Kinase Signalling
Authors: ---
Year: 2019 Publisher: MDPI - Multidisciplinary Digital Publishing Institute

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Starting from a kinase of interest, AMP-activated protein kinase (AMPK) has gone far beyond an average biomolecule. Being expressed in all mammalian cell types and probably having a counterpart in every eukaryotic cell, AMPK has attracted interest in virtually all areas of biological research. Structural and biophysical insights have greatly contributed to a molecular understanding of this kinase. From good old protein biochemistry to modern approaches, such as systems biology and advanced microscopy, all disciplines have provided important information. Thus, multiple links to cellular events and subcellular localizations have been established. Moreover, the crucial involvement of AMPK in human health and disease has been evidenced. AMPK accordingly has moved from an interesting enzyme to a pharmacological target. However, despite our extensive current knowledge about AMPK, the growing community is busier than ever. This book provides a snapshot of recent and current AMPK research with an emphasis on work providing molecular insight, including but not limited to novel physiological and pathological functions, or regulatory mechanisms. Up-to-date reviews and research articles are included.

Keywords

n/a --- HDACs --- transcription --- epigenetics --- spermatozoa --- par complex --- A769662 --- MDCK --- skeletal muscle --- AID --- phosphorylation --- energy metabolism --- monocytes --- autophagy --- CML --- liver --- hindlimb suspension --- pregnancy --- preeclampsia --- gestational diabetes mellitus --- CaMKK2 --- assisted reproduction techniques --- nutrient-sensing signals --- sonic hedgehog --- protein acetylation --- glycogen storage disease --- AMPK --- adenosine monophosphate-activated protein kinase --- AICAR --- indirect calorimetry --- IL-1? --- MyHC I(?) --- HDAC4/5 --- endothelial cells --- infection --- hepatocyte --- p70S6K --- lipid metabolism --- host defense --- exercise --- kidney disease --- heat shock protein --- ?RIM --- mycobacteria --- activation loop --- developmental origins of health and disease (DOHaD) --- CREB --- TAK1 --- metabolic-inflammation --- phenylephrine --- AMP-activated protein kinase (AMPK) --- KATs --- 2-methoxyestradiol --- DNA methylation --- NLRP3 --- pump --- ?-linker --- steatosis --- AMPK kinase --- stress --- endothelial nitric-oxide synthase --- vasodilation --- adherent junctions --- epithelial cells --- glycogen --- Akt --- synaptic activation --- cellular energy sensing --- glucose uptake --- transporter --- co-expression --- atrophy --- nutrigenomics --- motility --- vasoconstriction --- fatty acid oxidation --- oxidative stress --- AS160 --- membrane --- histone modification --- sirtuin 1 (SIRT1) --- chromatin remodeling --- insulin signalling --- dietary fatty acids --- ULK --- CMML --- adaptive thermogenesis --- mTOR --- MDS --- mechanical unloading --- AML --- endothelial function --- medulloblastoma --- PKA --- adipose tissue --- NAD+ --- membranes --- nutrition --- ZO-1 --- TBC1D4 --- adipocyte --- soluble Adenylyl cyclase --- metabolism --- renin-angiotensin system --- energy utilization --- proteasome --- differentiation --- signaling --- peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?) --- hypertrophy --- AMP-activated protein kinase --- metabolic disease --- LKB1 --- soleus muscle --- macrophages --- Immediate early genes --- CBS --- beiging --- motor endplate remodeling --- ionomycin --- nectin-afadin --- tight junctions --- resveratrol --- protein kinase B --- regrowth --- mitochondria --- protein synthesis --- energy deficiency --- catechol-O-methyltransferase --- fiber-type --- microarrays --- carrier --- acetyl-CoA --- hypertension --- 3T3-L1 --- hypothalamus --- food intake --- benign


Book
AMP-Activated Protein Kinase Signalling
Authors: ---
Year: 2019 Publisher: MDPI - Multidisciplinary Digital Publishing Institute

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Abstract

Starting from a kinase of interest, AMP-activated protein kinase (AMPK) has gone far beyond an average biomolecule. Being expressed in all mammalian cell types and probably having a counterpart in every eukaryotic cell, AMPK has attracted interest in virtually all areas of biological research. Structural and biophysical insights have greatly contributed to a molecular understanding of this kinase. From good old protein biochemistry to modern approaches, such as systems biology and advanced microscopy, all disciplines have provided important information. Thus, multiple links to cellular events and subcellular localizations have been established. Moreover, the crucial involvement of AMPK in human health and disease has been evidenced. AMPK accordingly has moved from an interesting enzyme to a pharmacological target. However, despite our extensive current knowledge about AMPK, the growing community is busier than ever. This book provides a snapshot of recent and current AMPK research with an emphasis on work providing molecular insight, including but not limited to novel physiological and pathological functions, or regulatory mechanisms. Up-to-date reviews and research articles are included.

Keywords

n/a --- HDACs --- transcription --- epigenetics --- spermatozoa --- par complex --- A769662 --- MDCK --- skeletal muscle --- AID --- phosphorylation --- energy metabolism --- monocytes --- autophagy --- CML --- liver --- hindlimb suspension --- pregnancy --- preeclampsia --- gestational diabetes mellitus --- CaMKK2 --- assisted reproduction techniques --- nutrient-sensing signals --- sonic hedgehog --- protein acetylation --- glycogen storage disease --- AMPK --- adenosine monophosphate-activated protein kinase --- AICAR --- indirect calorimetry --- IL-1? --- MyHC I(?) --- HDAC4/5 --- endothelial cells --- infection --- hepatocyte --- p70S6K --- lipid metabolism --- host defense --- exercise --- kidney disease --- heat shock protein --- ?RIM --- mycobacteria --- activation loop --- developmental origins of health and disease (DOHaD) --- CREB --- TAK1 --- metabolic-inflammation --- phenylephrine --- AMP-activated protein kinase (AMPK) --- KATs --- 2-methoxyestradiol --- DNA methylation --- NLRP3 --- pump --- ?-linker --- steatosis --- AMPK kinase --- stress --- endothelial nitric-oxide synthase --- vasodilation --- adherent junctions --- epithelial cells --- glycogen --- Akt --- synaptic activation --- cellular energy sensing --- glucose uptake --- transporter --- co-expression --- atrophy --- nutrigenomics --- motility --- vasoconstriction --- fatty acid oxidation --- oxidative stress --- AS160 --- membrane --- histone modification --- sirtuin 1 (SIRT1) --- chromatin remodeling --- insulin signalling --- dietary fatty acids --- ULK --- CMML --- adaptive thermogenesis --- mTOR --- MDS --- mechanical unloading --- AML --- endothelial function --- medulloblastoma --- PKA --- adipose tissue --- NAD+ --- membranes --- nutrition --- ZO-1 --- TBC1D4 --- adipocyte --- soluble Adenylyl cyclase --- metabolism --- renin-angiotensin system --- energy utilization --- proteasome --- differentiation --- signaling --- peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?) --- hypertrophy --- AMP-activated protein kinase --- metabolic disease --- LKB1 --- soleus muscle --- macrophages --- Immediate early genes --- CBS --- beiging --- motor endplate remodeling --- ionomycin --- nectin-afadin --- tight junctions --- resveratrol --- protein kinase B --- regrowth --- mitochondria --- protein synthesis --- energy deficiency --- catechol-O-methyltransferase --- fiber-type --- microarrays --- carrier --- acetyl-CoA --- hypertension --- 3T3-L1 --- hypothalamus --- food intake --- benign


Book
AMP-Activated Protein Kinase Signalling
Authors: ---
Year: 2019 Publisher: MDPI - Multidisciplinary Digital Publishing Institute

Loading...
Export citation

Choose an application

Bookmark

Abstract

Starting from a kinase of interest, AMP-activated protein kinase (AMPK) has gone far beyond an average biomolecule. Being expressed in all mammalian cell types and probably having a counterpart in every eukaryotic cell, AMPK has attracted interest in virtually all areas of biological research. Structural and biophysical insights have greatly contributed to a molecular understanding of this kinase. From good old protein biochemistry to modern approaches, such as systems biology and advanced microscopy, all disciplines have provided important information. Thus, multiple links to cellular events and subcellular localizations have been established. Moreover, the crucial involvement of AMPK in human health and disease has been evidenced. AMPK accordingly has moved from an interesting enzyme to a pharmacological target. However, despite our extensive current knowledge about AMPK, the growing community is busier than ever. This book provides a snapshot of recent and current AMPK research with an emphasis on work providing molecular insight, including but not limited to novel physiological and pathological functions, or regulatory mechanisms. Up-to-date reviews and research articles are included.

Keywords

HDACs --- transcription --- epigenetics --- spermatozoa --- par complex --- A769662 --- MDCK --- skeletal muscle --- AID --- phosphorylation --- energy metabolism --- monocytes --- autophagy --- CML --- liver --- hindlimb suspension --- pregnancy --- preeclampsia --- gestational diabetes mellitus --- CaMKK2 --- assisted reproduction techniques --- nutrient-sensing signals --- sonic hedgehog --- protein acetylation --- glycogen storage disease --- AMPK --- adenosine monophosphate-activated protein kinase --- AICAR --- indirect calorimetry --- IL-1? --- MyHC I(?) --- HDAC4/5 --- endothelial cells --- infection --- hepatocyte --- p70S6K --- lipid metabolism --- host defense --- exercise --- kidney disease --- heat shock protein --- ?RIM --- mycobacteria --- activation loop --- developmental origins of health and disease (DOHaD) --- CREB --- TAK1 --- metabolic-inflammation --- phenylephrine --- AMP-activated protein kinase (AMPK) --- KATs --- 2-methoxyestradiol --- DNA methylation --- NLRP3 --- pump --- ?-linker --- steatosis --- AMPK kinase --- stress --- endothelial nitric-oxide synthase --- vasodilation --- adherent junctions --- epithelial cells --- glycogen --- Akt --- synaptic activation --- cellular energy sensing --- glucose uptake --- transporter --- co-expression --- atrophy --- nutrigenomics --- motility --- vasoconstriction --- fatty acid oxidation --- oxidative stress --- AS160 --- membrane --- histone modification --- sirtuin 1 (SIRT1) --- chromatin remodeling --- insulin signalling --- dietary fatty acids --- ULK --- CMML --- adaptive thermogenesis --- mTOR --- MDS --- mechanical unloading --- AML --- endothelial function --- medulloblastoma --- PKA --- adipose tissue --- NAD+ --- membranes --- nutrition --- ZO-1 --- TBC1D4 --- adipocyte --- soluble Adenylyl cyclase --- metabolism --- renin-angiotensin system --- energy utilization --- proteasome --- differentiation --- signaling --- peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?) --- hypertrophy --- AMP-activated protein kinase --- metabolic disease --- LKB1 --- soleus muscle --- macrophages --- Immediate early genes --- CBS --- benign --- motor endplate remodeling --- ionomycin --- nectin-afadin --- tight junctions --- resveratrol --- protein kinase B --- regrowth --- mitochondria --- protein synthesis --- energy deficiency --- catechol-O-methyltransferase --- fiber-type --- microarrays --- carrier --- acetyl-CoA --- hypertension --- 3T3-L1 --- hypothalamus --- food intake --- HDACs --- transcription --- epigenetics --- spermatozoa --- par complex --- A769662 --- MDCK --- skeletal muscle --- AID --- phosphorylation --- energy metabolism --- monocytes --- autophagy --- CML --- liver --- hindlimb suspension --- pregnancy --- preeclampsia --- gestational diabetes mellitus --- CaMKK2 --- assisted reproduction techniques --- nutrient-sensing signals --- sonic hedgehog --- protein acetylation --- glycogen storage disease --- AMPK --- adenosine monophosphate-activated protein kinase --- AICAR --- indirect calorimetry --- IL-1? --- MyHC I(?) --- HDAC4/5 --- endothelial cells --- infection --- hepatocyte --- p70S6K --- lipid metabolism --- host defense --- exercise --- kidney disease --- heat shock protein --- ?RIM --- mycobacteria --- activation loop --- developmental origins of health and disease (DOHaD) --- CREB --- TAK1 --- metabolic-inflammation --- phenylephrine --- AMP-activated protein kinase (AMPK) --- KATs --- 2-methoxyestradiol --- DNA methylation --- NLRP3 --- pump --- ?-linker --- steatosis --- AMPK kinase --- stress --- endothelial nitric-oxide synthase --- vasodilation --- adherent junctions --- epithelial cells --- glycogen --- Akt --- synaptic activation --- cellular energy sensing --- glucose uptake --- transporter --- co-expression --- atrophy --- nutrigenomics --- motility --- vasoconstriction --- fatty acid oxidation --- oxidative stress --- AS160 --- membrane --- histone modification --- sirtuin 1 (SIRT1) --- chromatin remodeling --- insulin signalling --- dietary fatty acids --- ULK --- CMML --- adaptive thermogenesis --- mTOR --- MDS --- mechanical unloading --- AML --- endothelial function --- medulloblastoma --- PKA --- adipose tissue --- NAD+ --- membranes --- nutrition --- ZO-1 --- TBC1D4 --- adipocyte --- soluble Adenylyl cyclase --- metabolism --- renin-angiotensin system --- energy utilization --- proteasome --- differentiation --- signaling --- peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?) --- hypertrophy --- AMP-activated protein kinase --- metabolic disease --- LKB1 --- soleus muscle --- macrophages --- Immediate early genes --- CBS --- benign --- motor endplate remodeling --- ionomycin --- nectin-afadin --- tight junctions --- resveratrol --- protein kinase B --- regrowth --- mitochondria --- protein synthesis --- energy deficiency --- catechol-O-methyltransferase --- fiber-type --- microarrays --- carrier --- acetyl-CoA --- hypertension --- 3T3-L1 --- hypothalamus --- food intake

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