Deleting ACC1 in platelets alters phospholipidome and reduces platelet activation and thrombosis in mice

This study uncovers the pivotal role of acetyl-CoA carboxylase 1 (ACC1) in regulating platelet lipid composition, bioenergetics, activation, and thrombus formation, as demonstrated using a targeted glycoprotein Ibα (GPIbα)-Cre+/- mouse model. By comparing platelet-specific ACC1 knockout mice (GPIbα-Cre+/- × ACC1flx/flx) with both GPIbα-Cre+/- and ACC1flx/flx control groups, we showed that ACC1 deficiency profoundly reshaped the platelet phospholipidome. Specifically, ACC1 deletion led to decreased levels of arachidonic acid-containing phosphatidylethanolamine plasmalogens, thereby limiting thromboxane A2 synthesis, dense granule secretion, and platelet activation upon agonist stimulation. Bioenergetic analysis of ACC1-deficient platelets revealed reduced glycolytic activity, potentially worsening their activation defects. Notably, ACC1 deficiency also enhanced the mitochondrial reserve respiratory capacity, without altering basal respiration or adenosine triphosphate turnover. This increased reserve respiratory capacity correlated with reduced phosphatidylserine exposure, suggesting lower procoagulant activity. Importantly, we showed that ACC1 deficiency impaired thrombus formation without compromising hemostasis. Together, these findings identified ACC1 as a critical regulator of platelet function and highlighted its potential as a target for innovative antithrombotic therapies.