Acetyl-CoA carboxylase 1 deletion reduces platelet phospholipid and alters thrombus formation

Abstract

Acetyl-CoA carboxylase (ACC) is the key enzyme regulating de novo lipogenesis (DNL). In recent years, ACC inhibitors has been of great interest to handle a wide range of diseases, especially cancers and cardiovascular diseases. However, the impact of its inhibition on hemostasis and thrombosis remains under-investigated. We previously demonstrated that ACC1 activation promotes thrombus formation by increasing platelet phospholipid content and thromboxane A2 generation. Here, we sought to evaluate whether ACC1 platelet-specific deletion may affect platelet functions and by decreasing phospholipid content. To test this hypothesis we generated a new Cre transgenic mouse strain in which ACC1 is specifically deleted in megakaryocyte and platelet (GpIbCre±x ACC1 flx/flx mouse). Lipidomics analysis was carried out on the commercial Lipidyzer platform. Thromboxane A2 secretion was evaluated by ELISA. Platelet functions were assessed in vitro by aggregometry and ex vivo by flow chamber assay. Thrombus growth was analyzed in vivo with intravital microscopy. As expected, ACC1 deletion was restricted to megakaryocytic lineage. Hematological parameters show a platelet count decrease (30%) and a platelet volume increase (31%) in ACC1 knockout mice (ACC1 pKO) compared to the control mice. In agreement with our hypothesis, lipidomics analyses highlight a significant reduction in arachidonic acid containing phosphotidylethanolamine plasmalogen in ACC1 KO platelets. Logically, thromboxane A2 generation (upon thrombin or CRP stimulation) is also altered in ACC1 pKO mice in comparison to controls. This decrease in phospholipid content is associated with a default in thrombin and CRP-induced platelet aggregation and with impaired dense granules secretion. In line with these results, platelet-specific ACC1 deletion reduces thrombus growth and fibrinogen receptor activation. Platelet-specific ACC1 deletion leads to a decrease in phospholipid content which, in turn, decreases platelet thromboxane A2 generation, dense granules secretion and platelet aggregation. Thrombus formation is also reduced in platelet-specific ACC1 knockout mice, highlighting the importance of de novo lipogenesis and ACC-produced lipids in the regulation of platelet functions.