biostudies-literatureUnknownBarrachina MNNIDDK NIH HHSNHLBI NIH HHSWellcome TrustLipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in thrombocytopenia. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production, and that changes in dietary fatty acids may be a novel and viable target to modulate platelet counts.bioRxiv : the preprint server for biology2023.02.12.527706https://www.ebi.ac.uk/biostudies/studies/S-EPMC9934665biostudies-literatureEfficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.PMC9934665R01 HL151494R01 DK112778T32 HL007734R35 HL161175R03 DK124746218649/Z/19/ZCollins TJLuyendyk JBoilard EMachlus KRAllaeys IMurphy AJFreire DAlmazni IGroeneveld DJWei ZItaliano JEMellett NAMorgan NVHirsch TIKhan AOGuo KPuder MCarminita EMeikle PJBarrachina MNBecker ICMorgan PKPernes GfalseEfficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.Lipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in thrombocytopenia. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production, and that changes in dietary fatty acids may be a novel and viable target to modulate platelet counts.2023-01-01T00:00:00Z2023 Feb2026-04-07T13:32:22.673Z2026-04-07T13:23:48.741ZS-EPMC99346653679833210.1101/2023.02.12.527706