Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation.

Marie Octave,Valentine Robaux,Marc Foretz,Sophie Lepropre,Martin Giera,Caroline Bouzin,Jérôme Ambroise,Luc Bertrand,Bruno Guigas,Christophe Beauloye,Audrey Ginion,Sandrine Horman,Laurence Pirotton

doi:10.3390/ijms222313129

Marie Octave, Valentine Robaux + Show 11 more

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https://doi.org/10.3390/ijms222313129

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Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton.

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Acetyl-CoA carboxylase (ACC) catalyzes the first step of de novo lipogenesis (DNL) by carboxylating acetyl-CoA into malonyl-CoA [1]
We focused on the impact of the pharmacological ACC inhibitor, CP640.186, on the acetylation status of tubulin in human platelets
We first investigated whether short-term pharmacological ACC inhibition would be able to reduce DNL in human platelets

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Acetyl-CoA carboxylase (ACC) catalyzes the first step of de novo lipogenesis (DNL) by carboxylating acetyl-CoA into malonyl-CoA [1]. ACC1 provides a pool of cytosolic malonyl-CoA, which serves as a substrate for fatty acid synthase and chain elongation systems. ACC2 produces malonyl-CoA near the mitochondrial membrane where it acts as an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1); this enzyme is responsible for transporting long-chain fatty acids into mitochondria [3,4,5]. We previously demonstrated that ACC1 is the predominant isoform in murine and human platelets [7]. ACC1 promotes thrombosis through platelet phospholipid production, which is required for the synthesis of arachidonic acid (AA), a key mediator of platelet activation [7]. The presence of ACC in DNL has been implicated in megakaryocyte (MK) maturation and platelet production [8]

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