Elevated Plasma PCSK9 Is Equally Detrimental for Non-Familial Hypercholesterolemic (Non-FH) and Heterozygous FH Patients, Irrespective of Their LDL Receptor Defects

Study Questions:

What is the risk of elevated PCSK9 levels in subjects with reduced low-density lipoprotein receptor (LDLR) levels?


Circulating PCSK9 was measured by enzyme-linked immunosorbent assay (ELISA) in nontreated heterozygous familial hypercholesterolemic (HeFH) patients carrying LDLR missense mutations (n = 392) and in normolipidemic controls (n = 152). Skin fibroblasts and lymphocytes were isolated from patients and treated with mevastatin and increasing amounts of recombinant PCSK9. LDLR abundance at the cell surface was determined by flow cytometry.


PCSK9 dose dependently reduced LDLR expression in control and FH fibroblasts to similar extents, by up to 77 ± 8% and 82 ± 7%. Likewise, PCSK9 reduced LDLR abundance by 39 ± 8% in non-FH and by 45 ± 10% in HeFH lymphocytes, irrespective of their LDLR mutation status. Positive correlations were observed between PCSK9 and LDL cholesterol in control and HeFH patients that were similar in magnitude.


The authors concluded that elevated PCSK9 levels are equally detrimental for HeFH and non-FH patients.


Inhibition of PCSK9 represents a promising treatment for patients with refractory hyperlipidemia such as those with HeFH. Although statins increase LDLR expression, they also increase PCSK9 levels, which may blunt the LDL-lowering effect of statins. The effect of PCSK9 on LDLR expression and LDL clearance in patients with HeFH is unclear due to the baseline genetic reduction in LDLR. This study confirms that PCSK9 plays an important regulatory role towards LDLR expression and LDL clearance in HeFH patients. This is consistent with clinical studies that have demonstrated effectiveness of PCSK9 inhibition in this patient population.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Mutation, Missense, Cholesterol, LDL, Fibroblasts, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Receptors, LDL, Enzyme-Linked Immunosorbent Assay, Proprotein Convertases, Lipoproteins, LDL, Dyslipidemias, Biological Markers, Lymphocytes, Troponin I, Serine Endopeptidases, Heterozygote

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