In a landmark study, scientists discovered what makes white blood cell counts spike in individuals who have high cholesterol, possibly leading to new therapies for heart disease.
The team looked at hypercholesterolemia, which is the type of high cholesterol that causes very high levels of LDL - the so-called "bad" cholesterol - to circulate in the blood. They identified a new regulatory mechanism in zebrafish models responsible for this increase in white blood cells typically seen in people with these high LDL levels, which are known to increase a person's risk for cardiovascular disease, the leading cause of morbidity and mortality in the U.S. and globally.
The authors report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence.
Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects.
"Our findings may explain why this can happen," the senior author said. "This mechanism we identified activates a protein called SREBP2 that in turn leads to the development of more hematopoietic stem cells (HSPCs), which are the precursors to white blood cells and the process by which all mature blood cells are produced. We were able to show that targeting this protein using its antagonist can reduce the HSPC counts to bring down the white blood cell counts. This insight may lead to a new strategy to treat atherosclerotic cardiovascular disease."
Additionally, finding this new pathway that controls the generation of HSPCs could be useful for treating blood disorders, such as leukemia and anemia, in the future. For instance, the plant-derived drug betulin, which is an SREBP2 inhibitor, could possibly be repurposed to mitigate the progression of leukemia. Even further down the line, this also holds promise for bone marrow regeneration using patient-derived hematopoietic stem cells, which would eliminate the need to find a donor.
The authors say their next steps are to continue exploring the role of cholesterol metabolism in hematopoiesis, saying that their findings bring them one step closer to their ultimate goal of generating patient-oriented HSPCs, which will be essential for the progress of regenerative and precision medicine.
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