Elevated Plasma PCSK9 Level Is Equally Detrimental for Patients With Nonfamilial Hypercholesterolemia and Heterozygous Familial Hypercholesterolemia, Irrespective of Low-Density Lipoprotein Receptor Defects

Lambert, Gilles; Petrides, Francine; Chatelais, Mathias; Blom, Dirk; Choque, Benjamin; Tabet, Fatiha; Wong, Gida; Rye, Kerry‐Anne; Hooper, Amanda J.; Burnett, John R.; Barter, Philip J.; Marais, A. David

doi:10.1016/j.jacc.2014.02.538

Cited by 57 publications

(38 citation statements)

References 29 publications

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“…Cell supernatants were cleared by centrifugation at 4°C for 10 min at 10,000 ϫ g. PCSK9 concentrations were measured in duplicate in supernatant from HepG2 and Huh7 cells with a SPC900 Quantikine enzyme-linked immunosorbent assay (ELISA) kit (R&D System, Lille, France), as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

Loregger

Cook

Nelson

et al. 2016

Molecular and Cellular Biology

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Cholesterol synthesis and lipoprotein uptake are tightly coordinated to ensure that the cellular level of cholesterol is adequately maintained. Hepatic dysregulation of these processes is associated with pathological conditions, most notably cardiovascular disease. Using a genetic approach, we have recently identified the E3 ubiquitin ligase MARCH6 as a regulator of cholesterol biosynthesis, owing to its ability to promote degradation of the rate-limiting enzymes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE). Here, we present evidence for MARCH6 playing a multifaceted role in the control of cholesterol homeostasis in hepatocytes. We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program. Accordingly, loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. Unexpectedly, this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR). Finally, we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6-induced phenotype. Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake. Cholesterol is an essential constituent of cellular membranes and signaling pathways and is a precursor of sterol-derived molecules (1). Yet elevated levels of cholesterol are toxic to cells, and dysregulated cholesterol metabolism is associated, most evidently, with development of cardiovascular disease. As such, multiple transcriptional networks and posttranscriptional processes regulate the synthesis, uptake, and efflux of cholesterol. Transcriptionally, these processes are largely governed by the opposing actions of the transcription factors sterol regulatory element binding proteins (SREBPs) and the liver X receptors (LXRs) (2-6). Upon sensing low cholesterol levels in the endoplasmic reticulum (ER), SREBPs are processed into their mature, transcriptionally active form. This results in induction of the full set of genes required for de novo biosynthesis of cholesterol via the mevalonate pathway and of the low-density lipoprotein receptor (LDLR) that is required for uptake of LDL-derived cholesterol (7, 8). In contrast, LXRs, members of the nuclear receptor family, are activated when cellular cholesterol levels are elevated. Once activated by their cognate oxysterol ligands, LXRs induce cholesterol efflux pathways (e.g., via the transporters ABCA1 and ABCG1) and limit LDL uptake by inducing expression of the E3 ubiquitin ligase (E3)-inducible degrader of the LDLR (IDOL) (6, 9, 10). The coordinated action of these two transcription factor families ensures that cellular cholesterol is adequately maintained at an appropriate level.Next to transcriptional regulation, posttranscriptional mechanisms are ...

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Section: Methodsmentioning

confidence: 99%

A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

Loregger

Cook

Nelson

et al. 2016

Molecular and Cellular Biology

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“…4,12 We showed that ARH fibroblasts respond almost just as well to statins, PCSK9, and alirocumab than control fibroblasts, in terms of cell surface LDLR expression ( Figure …”

Section: Resultsmentioning

confidence: 84%

“…Circulating PCSK9 levels were extremely elevated in ARH at 526±31 ng/mL. 11,12 We first assessed cell-surface LDLR expression in lymphocytes isolated from control individuals and ARH patients by flow cytometry. After mevastatin treatment, ∆ mean fluorescence intensity (MFI) levels of cell surface LDLR expression reached a maximum of 635±56 arbitrary unit (AU) in control lymphocytes.…”

Section: Resultsmentioning

confidence: 99%

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report

Thedrez

Sjouke

Passard

et al. 2016

ATVB

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Objective— Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results— Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. Conclusions— PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.

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“…The authors compared ex vivo LDLR expression on the cell surface of lymphocytes (an accepted surrogate of hepatocyte LDLR expression) 17 in 22 HoFH patients with 1 normolipidemic individual and 5 HeFH patients. Experiments followed a rigorous sequence previously used by the authors 18 that simulate lipid-lowering treatments usually prescribed to FH patients, including stimulation of LDLR expression by 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibition with mevastatin, incubation with recombinant PCSK9 to facilitate LDLR degradation, and incubation with a PCSK9 neutralizing antibody.…”

Section: See Accompanying Article On Page 592mentioning

confidence: 99%

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

Santos

2018

ATVB

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Elevated Plasma PCSK9 Level Is Equally Detrimental for Patients With Nonfamilial Hypercholesterolemia and Heterozygous Familial Hypercholesterolemia, Irrespective of Low-Density Lipoprotein Receptor Defects

Cited by 57 publications

References 29 publications

A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

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