Multiparametric assessment of cellular lipid metabolism in hypercholesterolemia

Differences in cellular lipid metabolism may underlie large interindividual variability in lipid disorders such as hypercholesterolemia. Here, we established a multi-parametric imaging platform enabling the quantification of lipid uptake and storage in cytoplasmic droplets of leukocyte populations from 2-4 ml of peripheral blood. We define a new quantifiable parameter, cellular lipid mobilization, describing the efficiency at which cells deplete their lipid reservoirs. The 65 individuals studied, including heterozygous familial hypercholesterolemia (He-FH) patients with identical LDL receptor mutations, showed distinct profiles of low-density lipoprotein (LDL) uptake and lipid mobilization. Lipid mobilization correlated positively with cellular LDL uptake and negatively with hypercholesterolemia, increased body mass index and age. Lipid mobilization and LDL uptake distinguished good and poor statin responders among He-FH patients, and their combination with polygenic scores improved the risk assessment in hypercholesterolemia within a general population subcohort. Together, these findings open up new avenues for personalized medicine approaches in hypercholesterolemia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/440471v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@eb2968org.highwire.dtl.DTLVardef@eb84f5org.highwire.dtl.DTLVardef@6628b0org.highwire.dtl.DTLVardef@f9692d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Schematic illustration of functional readouts in peripheral blood mononuclear cells and their correlation with physiological outcomes in monogenic and polygenic hypercholesterolemia. C_FIG