AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation

Abstract

AMP-activated protein kinase (AMPK) α1 is activated in platelets on thrombin or collagen stimulation, and as a consequence, phosphorylates and inhibits acetyl-CoA carboxylase (ACC). Because ACC is crucial for the synthesis of fatty acids, which are essential for platelet activation, we hypothesized that this enzyme plays a central regulatory role in platelet function. To investigate this, we used a double knock-in (DKI) mouse model in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser212 on ACC2 were mutated to prevent AMPK signaling to ACC. Suppression of ACC phosphorylation promoted injury-induced arterial thrombosis in vivo and enhanced thrombus growth ex vivo on collagen-coated surfaces under flow. After collagen stimulation, loss of AMPK-ACC signaling was associated with amplified thromboxane generation and dense granule secretion. ACC DKI platelets had increased arachidonic acid-containing phosphatidylethanolamine plasmalogen lipids. In conclusion, AMPK-ACC signaling is coupled to the control of thrombosis by specifically modulating thromboxane and granule release in response to collagen. It appears to achieve this by increasing platelet phospholipid content required for the generation of arachidonic acid, a key mediator of platelet activation.

Platelet lipidome: Dismantling the “Trojan horse” in the bloodstream

“…At a later stage of activation, when FAs become limiting, mitochondrial β‐oxidation is retarded, ATP consuming maintenance of membrane asymmetry is compromised, leading to the exposure of procoagulant PS, otherwise confined to the inner leaflet of plasma membrane . Another investigation validates the utility of lipogenesis in platelet bioenergetics . Acetyl Co‐A‐carboxylase (ACC), a key regulator of FA metabolism when in (ACC1) cytosol synthesizes malonyl‐Co‐A for de novo lipogenesis; whereas ACC2 on the outer mitochondrial membrane prevents FA transport into mitochondria.…”

“…A considerable enrichment of AA containing PE‐plasmalogens (16:0/20:4, 18:1/20:4) is also observed upon the gain of ACC function. This, together with a concomitant increase in TxA2 synthesis, confers a prothrombotic phenotype in ACC1/2DKI mice. Angiotensin II‐induced abdominal aortic aneurysm (AAA) models in ApoE −/− mice also show elevated levels of HETE‐PL (12‐, 5‐, 15‐HETE‐PEs and PCs) along with several eoxPLs, eg, HODE, HDOHE, and non=enzymatic fragments of eoxPLs, that substantiate procoagulant functions .…”

“…AMPK phosphorylates and inactivates ACC possibly to halt energy‐demanding lipogenesis and release the brake on FA channeling into the mitochondrial powerhouse. Absence of an AMPK‐ACC inactivation axis exaggerates thrombotic response to collagen but has no bearing on basal or thrombin and collagen stimulated bioenergetics . Exogenous plasma energy reserves may also influence platelet bioenergetics.…”

“…7 Another investigation validates the utility of lipogenesis in platelet bioenergetics. 49 Acetyl Co-Acarboxylase (ACC), a key regulator of FA metabolism when in (ACC1) cytosol synthesizes malonyl-Co-A for de novo lipogenesis; whereas ACC2 on the outer mitochondrial membrane prevents FA transport into mitochondria. AMPK, which is sensitive to ATP depletion and rise in AMP levels, is activated upon platelet stimulation.…”

“…Absence of an AMPK-ACC inactivation axis exaggerates thrombotic response to collagen but has no bearing on basal or thrombin and collagen stimulated bioenergetics. 49 Exogenous plasma energy reserves may also influence platelet bioenergetics. Guppy et al 50 addressed metabolic fuel consumption by platelets from plasma and estimated an ATP turnover of 25 µmol/10 10 platelets/h, a quarter of which is attributed to aerobic glycolysis and the rest to oxidation of various substrates.…”