Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

Familial hypercholesterolaemia ( FH ) is a major risk for premature coronary heart disease due to severe long‐life exposure to high LDL levels. Accumulation of LDL in the vascular wall triggers atherosclerosis with activation of the innate immunity system. Here, we have investigated (i) gene expression of LDLR and LRP s in peripheral blood cells ( PBL s) and in differentiated macrophages of young FH ‐patients; and (ii) whether macrophage from FH patients have a differential response when exposed to high levels of atherogenic LDL . PBL s in young heterozygous genetically characterized FH patients have higher expression of LRP 5 and LRP 6 than age‐matched healthy controls or patients with secondary hypercholesterolaemia. LRP 1 levels were similar among groups. In monocyte‐derived macrophages ( MAC s), LRP 5 and LRP 1 transcript levels did not differ between FH s and controls in resting conditions, but when exposed to ag LDL , FH ‐ MAC showed a highly significant up‐regulation of LRP 5 , while LRP 1 was unaffected. PBL and MAC cells from FH patients had significantly lower LDLR expression than control cells, independently of the lipid‐lowering therapy. Furthermore, exposure of FH ‐ MAC to ag LDL resulted in a reduced expression of CD 163 , scavenger receptor with anti‐inflammatory and atheroprotective properties. In summary, our results show for first time that LRP s, active lipid‐internalizing receptors, are up‐regulated in innate immunity cells of young FH patients that have functional LDLR mutations. Additionally, their reduced CD 163 expression indicates less atheroprotection. Both mechanisms may play a synergic effect on the onset of premature atherosclerosis in FH patients.