OC 10.1 - CD36-dependent metabolic rewiring and mitochondrial dysfunction in platelets in response to hyperlipidaemia.

Background: Atherogenic hyperlipidaemia leads to plasma oxidised low-density lipoprotein (oxLDL) accumulation, associated with increased arterial thrombosis. Scavenger receptor CD36 translates oxidised lipid stress to platelet hyperactivity via oxLDL binding. Platelet hyperactivation requires energy, however, the effects of oxLDL on metabolic rewiring remains elusive.

Aims: Investigate the effects of oxLDL on metabolic rewiring and mitochondrial dysfunction.

Methods: Mice with platelet specific deletion of CD36 (CD36fl/fl/PF4cre) were used in comparison to CD36fl/fl littermates. Hyperlipidaemic mice were produced by high fat diet (HFD) feeding (20 weeks). To mimic these effects in vitro, oxLDL or native-LDL (nLDL) was used.

Results: CD36fl/fl/PF4cre mice were fertile with no differences found in platelet counts and key haemostatic receptors expression. The metabolically disturbed environment of HFD led to whole body hyperlipidaemia and insulin resistance. Under these conditions, CD36fl/fl platelets were shown to increase glucose uptake, which was lost in CD36fl/fl/PF4cre. Increased glucose uptake was associated with elevated basal glycolysis which was CD36 dependent. Upon thrombin stimulation, glycolysis and glucose uptake were further enhanced in CD36fl/fl platelets. Interestingly, glycolysis but not glucose uptake was attenuated in CD36fl/fl/PF4cre. When CD36fl/fl platelets were oxLDL-treated there was a significantly higher glucose uptake than nLDL, and this was lost in CD36fl/fl/PF4cre mice. The accumulation of TMRE dye (mitochondrial polarity marker) was higher in HFD platelets however it was reduced in CD36fl/fl/PF4cre compared to the CD36fl/fl platelets. This effect was phenocopied in oxLDL-treated human platelets. Mitochondrial superoxide production were also increased in hyperlipidaemia and oxLDL treatment. Importantly the effects of oxLDL on glucose uptake and mitochondrial function were reduced by glycolytic inhibitors.

Conclusion(s): We have previously shown that activated platelets are highly glycolytic. However, under conditions of hyperlipidaemia that glucose metabolism is elevated and results in mitochondrial function alterations. These effects are CD36 dependent and likely to occur via interaction with oxLDL.
This work was funded by BHF (RG/16/5/32250).