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

Rafael Escate,Lina Badimon,Rosa Suades,Maria Borrell‐Pages,Rosa Aledo,Pedro Mata,Teresa Padro

doi:10.1111/jcmm.12993

Abstract

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 LRPs in peripheral blood cells (PBLs) 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. PBLs in young heterozygous genetically characterized FH patients have higher expression of LRP5 and LRP6 than age‐matched healthy controls or patients with secondary hypercholesterolaemia. LRP1 levels were similar among groups. In monocyte‐derived macrophages (MACs), LRP5 and LRP1 transcript levels did not differ between FHs and controls in resting conditions, but when exposed to agLDL, FH‐MAC showed a highly significant up‐regulation of LRP5, while LRP1 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 agLDL resulted in a reduced expression of CD163, scavenger receptor with anti‐inflammatory and atheroprotective properties. In summary, our results show for first time that LRPs, active lipid‐internalizing receptors, are up‐regulated in innate immunity cells of young FH patients that have functional LDLR mutations. Additionally, their reduced CD163 expression indicates less atheroprotection. Both mechanisms may play a synergic effect on the onset of premature atherosclerosis in FH patients.

Highlights

Familial hypercholesterolaemia (FH) is an inherited disorder characterized by high concentration of plasma low-density lipoprotein (LDL) cholesterol levels, as result of mutations in the LDL receptor (LDLR) that impair liver LDL clearance [1, 2], and less frequently by genetic defects in the apolipoprotein B-100 (Apo B) or the protease PCSK9 [3]
To explore whether transcriptional levels of cell-membrane receptors involved in LDL uptake are affected in the peripheral blood cells (PBLs) fraction of FH patients, we analysed mRNA -expression of LRP1, LRP5, LDLR and Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) by real-time PCR in the three groups of young individuals, with an average age of 35 years
PBL from FH-LLTÀ patients showed higher LRP5 gene expression than those from the FH-lipid-lowering treatment (LLT)+ group (P = 0.016), LDL-c levels did not differ significantly between FH-LLT+ and FH-LLTÀ groups

Summary

Introduction

Familial hypercholesterolaemia (FH) is an inherited disorder characterized by high concentration of plasma low-density lipoprotein (LDL) cholesterol levels, as result of mutations in the LDL receptor (LDLR) that impair liver LDL clearance [1, 2], and less frequently by genetic defects in the apolipoprotein B-100 (Apo B) or the protease PCSK9 [3]. The atherosclerotic process, initiated by the accumulation of lipids LDL in the subendothelial space, proceeds with activation of local inflammation and the innate immunity response [10]. Macrophages are the main innate immunity cellular component of atherosclerotic plaques, leading to the proinflammatory response [17, 18]. There are at least two distinct subtypes of macrophages (M1 and M2) [19]; the M2-macrophage phenotype is characterized by a high cell surface expression of CD163 [20], a scavenger receptor associated to oxidative stress resistance [21]

Methods

Results

Conclusion