The impact of cholesterol metabolism on megakaryopoiesis and platelet production. (LSBR 0912 Fellowshipproject)
Project leader: Dr. Suzanne J.A. Korporaal, Dept. of Clinical Chemistry and Haematology, University Medical Center Utrecht and Prof. dr. Miranda van Eck, Division Biopharmaceutics, LACDR
Postdoc: Suzanne J.A. Korporaal PhD (Jan. 2011 – Nov. 2015)
Ph.D. student: Marti Boss, MSc (Oct. 2010 – Jan. 2011)
Ph.D. student: Marco van der Stoep, MSc (Mar. 2012 – Mar. 2016)
Platelet transfusions are life-saving procedures in preventing or treating complications resulting from bleeding and hemorrhage in patients with disorders associated with low platelet count or platelet dysfunction. During transfusion, it is essential to prevent platelet activation and early platelet destruction by macrophages. It is thus essential to learn more about platelet characteristics and factors involved in platelet activation. Platelets are produced by megakaryocytes. These progenitor cells require cholesterol to grow and mature and to eventually produce platelets. A better understanding of the association of cholesterol metabolism with platelet production and function is thus essential and may help to improve storage conditions that will increase platelet survival in vivo after transfusion.
The studies performed in this project have shown that a defect in cholesterol uptake by megakaryocytes due to the absence of low-density lipoprotein (LDL) receptor (LDLr) or a defect in cholesterol efflux due to a defect in ATP-binding cassette transporters like ABCA1 and/or ABCG1 causes impaired megakaryocyte maturation and platelet formation. Hence, the intracellular cholesterol content in Mks is an important determinant of platelet formation.
It has long been believed that an excess of cholesterol in plasma leads to hyperreactive platelets. Although this is true for many platelet activators, the current research project has shown that platelets from mice or humans with elevated plasma cholesterol levels contain higher intracellular cholesterol levels and as a result display a reduced response to collagen, a constituent of the vessel wall. Knowledge of the mechanism behind this dampened platelet response may lead to the discovery of new ways to keep platelets in a resting state during storage for transfusion. Additionally, it may reveal new targets in the treatment of cardiovascular disease.
The lower response to collagen may be either caused by a defective collagen receptor GPVI, or may find its origin in the cholesterol-sensing protein Liver X Receptor (LXR). Activation of this protein limits the build-up of pathogenic levels of cholesterol in macrophages of the arterial wall by stimulating cholesterol efflux, and also reduces atherosclerotic plaque size. LXR is also present in platelets, despite the lack of a genome. In platelets, LXR interacts with proteins of the collagen-induced signaling pathway in plateletscausing a decrease in platelet activation in response to collagen. In nucleated cells, LXR is complexed to FHL2, resulting in the modulation of the gene transcription-regulating function of FHL2. We discovered that the complex is also present in platelets, suggesting a regulatory role for FHL2 with regard to LXR activity.
Overall, the findings of project #0912F have demonstrated the impact of cholesterol on platelet production, as well as on platelet function. Our data have shown that hyperlipidemia is not necessarily associated with hyperreactive platelets, but also induces a reduction in reactivity to collagen, either caused by defective GPVI, or by the effect of cholesterol on the activity of the cholesterol-sensing LXR. This knowledge in itself will not directly change current storage conditions of platelets intended for transfusion, but may help in exploring the optimal conditions to keep platelets in a resting state before transfusion.