Platelet acetyl-CoA carboxylase phosphorylation: A risk stratification marker that reveals platelet-lipid interplay in coronary artery disease patients

Abstract

Activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) leads to phosphorylation of acetyl-CoA carboxylase (ACC) on serine 79 (phosphoACC) and its subsequent inhibition. Given the role of AMPK-ACC signaling in platelet lipid metabolism and function, this pathway could be affected in the platelets of patients with coronary artery disease (CAD), where the atherogenic environment has an impact on platelet biology. We hypothesized that platelet AMPKACC signaling is activated by atherogenic lipids and could be considered as a metabolic signature in high-risk CAD patients. We also explored the consequences of platelet phosphoACC on platelet lipid metabolic profile. Blood samples from 188 consecutive patients admitted for coronary angiography were processed. Lipid extracts from the platelets of 31 patients were subjected to lipidomic analysis. PhosphoACC level in circulating platelets of CAD patients were significantly increased and was linked to the severity of coronary artery calcification as well as acute coronary syndrome (OR: 6.71, 95% CI: 2.06–21.91; P = 0.002). The triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio, a well-known atherogenic marker, was strongly associated with increased phosphoACC in our CAD cohort. Hence, oxLDL activated AMPK-ACC signaling through a CD36-dependent pathway. Lipidomic analysis revealed that increased phosphoACC led to a down-regulation of intraplatelet TG, particularly of those containing C14:0 fatty acid chains. Platelet phosphoACC is a marker for risk stratification in suspected CAD patients and reveals an interaction between platelets and lipids. Inhibitory phosphoACC impacts platelet lipid content by down-regulating TG, which in turn may affect platelet function (ACCTHEROMA, NCT03034148).