Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

Gonzalo-Calvo, David de; Cenarro, Ana; Martínez-Bujidos, M.; Badimon, Lina; Bayés‐Genís, Antoni; Ordóñez-Llanos, Jordi; Civeira, Fernando; Llorente‐Cortés, Vicenta

doi:10.1016/j.ijcard.2015.07.085

Cited by 35 publications

(37 citation statements)

References 69 publications

(96 reference statements)

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“…As for LRP1, it is only known that the LRP1 protein itself can be further processed releasing a soluble LRP1 form. Shedding increases during ageing and is dysregulated in disease wherefore it is abundantly present in brain tissue and cerebrospinal fluid as well as in serum and plasma [48–50]. The released extracellular part of LRP1 (515 and 55 kDa) [51] is still able to bind ligands.…”

Section: Discussionmentioning

confidence: 99%

Verification and characterization of an alternative low density lipoprotein receptor-related protein 1 splice variant

Kolb¹,

Kurz²,

Schäfer³

et al. 2017

PLoS ONE

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BackgroundLow density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a ubiquitously expressed multi-ligand endocytosis receptor implicated in a wide range of signalling, among others in tumour biology. Tumour-associated genomic mutations of the LRP1 gene are described, but nothing is known about cancer-associated expression of LRP1 splice variants Therefore, the focus of this study was on an annotated truncated LRP1 splice variant (BC072015.1; NCBI GenBank), referred to as smLRP1, which was initially identified in prostate and lung carcinoma.MethodsUsing PCR and quantitative PCR, the expression of LRP1 and smLRP1 in different human tissues and tumour cell lines was screened and compared on tumour biopsies of head and neck squamous cell carcinoma (HNSCC). Using a recently developed anti-smLRP1 antibody, the expression of the putative LRP1 protein isoform in tumour cell lines in Western blot and immunofluorescence staining was further investigated.ResultsThe alternative transcript smLRP1 is ubiquitously expressed in 12 human cell lines of different origin and 22 tissues which is similar to LRP1. A shift in expression of smLRP1 relative to LRP1 towards smLRP1 was observed in most tumour cell lines compared to healthy tissue. The expression of LRP1 as well as smLRP1 is decreased in HNSCC cell lines in comparison to healthy mucosa. In vitro results were checked using primary HNSCC. Furthermore, the expression of the protein isoform smLRP1 (32 kDa) was confirmed in human tumour cell lines.ConclusionsSimilar to LRP1, the truncated splice variant smLRP1 is ubiquitously expressed in healthy human tissues, but altered in tumours pointing to a potential role of smLRP1 in cancer. Comparative results suggest a shift in expression in favour of smLRP1 in tumour cells that warrant further evaluation. The protein isoform is suggested to be secreted.

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Section: Discussionmentioning

confidence: 99%

Verification and characterization of an alternative low density lipoprotein receptor-related protein 1 splice variant

Kolb¹,

Kurz²,

Schäfer³

et al. 2017

PLoS ONE

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“…The importance of circulating soluble LRP1 (sLRP1) protein level as a potential biomarker of hypercholesterolemia was indicated by the higher sLRP1 levels in patients with severe hypercholesterolemia compared to those with moderate elevation or normal levels of serum cholesterol [68]. LRP1 gene variants are shown to be the predictors of cardiovascular disease risk in patients with FH [69].…”

Section: Genetic Basis Of Polygenic Hypercholesterolemia – the Genes mentioning

confidence: 99%

Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

2017

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Hypercholesterolemia is a strong determinant of mortality and morbidity associated with cardiovascular diseases and a major contributor to the global disease burden. Mutations in four genes (LDLR, APOB, PCSK9 and LDLRAP1) account for the majority of cases with familial hypercholesterolemia. However, a substantial proportion of adults with hypercholesterolemia do not have a mutation in any of these four genes. This indicates the probability of having other genes with a causative or contributory role in the pathogenesis of hypercholesterolemia and suggests a polygenic inheritance of this condition. Here in, we review the recent evidence of association of the genetic variants with hypercholesterolemia and the three lipid traits; total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C), their biological pathways and the associated pathogenetic mechanisms. Nearly 80 genes involved in lipid metabolism (encoding structural components of lipoproteins, lipoprotein receptors and related proteins, enzymes, lipid transporters, lipid transfer proteins, and activators or inhibitors of protein function and gene transcription) with single nucleotide variants (SNVs) that are recognized to be associated with hypercholesterolemia and serum lipid traits in genome-wide association studies and candidate gene studies were identified. In addition, genome-wide association studies in different populations have identified SNVs associated with TC, HDL-C and LDL-C in nearly 120 genes within or in the vicinity of the genes that are not known to be involved in lipid metabolism. Over 90% of the SNVs in both these groups are located outside the coding regions of the genes. These findings indicates that there might be a considerable number of unrecognized processes and mechanisms of lipid homeostasis, which when disrupted, would lead to hypercholesterolemia. Knowledge of these molecular pathways will enable the discovery of novel treatment and preventive methods as well as identify the biochemical and molecular markers for the risk prediction and early detection of this common, yet potentially debilitating condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-017-0488-4) contains supplementary material, which is available to authorized users.

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“…The levels of circulating sLRP1 are significantly higher in patients with severe hypercholesterolaemia than in patients with moderate hypercholesterolaemia and normocholesterolemic controls . The association between circulating sLRP1 levels and pro‐atherogenic lipoproteins, including LDL cholesterol, is reproducible in different hypercholesterolaemic populations, suggesting their causality.…”

Section: Discussionmentioning

confidence: 99%

“…Low‐density lipoprotein (LDL) receptor‐related protein 1 (LRP1) is a multifunctional receptor of the LDL receptor family that mediates the clearance of a variety of structurally diverse extracellular molecules . LRP1 has a soluble form (sLRP1) , which can be detected in the systemic circulation and other biofluids . sLRP1 is composed of the α chain and a ~55‐kDa fragment of the β chain and is generated by endoproteolysis of the membrane β chain segment .…”

Section: Introductionmentioning

confidence: 99%

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Extracellular vesicles do not contribute to higher circulating levels of soluble LRP1 in idiopathic dilated cardiomyopathy

Roura

Gálvez‐Montón

Gonzalo‐Calvo

et al. 2017

J Cellular Molecular Medi

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Idiopathic dilated cardiomyopathy (IDCM) is a frequent cause of heart transplantation. Potentially valuable blood markers are being sought, and low‐density lipoprotein receptor‐related protein 1 (LRP1) has been linked to the underlying molecular basis of the disease. This study compared circulating levels of soluble LRP1 (sLRP1) in IDCM patients and healthy controls and elucidated whether sLRP1 is exported out of the myocardium through extracellular vesicles (EVs) to gain a better understanding of the pathogenesis of the disease. LRP1 α chain expression was analysed in samples collected from the left ventricles of explanted hearts using immunohistochemistry. sLRP1 concentrations were determined in platelet‐free plasma by enzyme‐linked immunosorbent assay. Plasma‐derived EVs were extracted by size‐exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis and cryo‐transmission electron microscopy. The distributions of vesicular (CD9, CD81) and myocardial (caveolin‐3) proteins and LRP1 α chain were assessed in SEC fractions by flow cytometry. LRP1 α chain was preferably localized to blood vessels in IDCM compared to control myocardium. Circulating sLRP1 was increased in IDCM patients. CD9‐ and CD81‐positive fractions enriched with membrane vesicles with the expected size and morphology were isolated from both groups. The LRP1 α chain was not present in these SEC fractions, which were also positive for caveolin‐3. The increase in circulating sLRP1 in IDCM patients may be clinically valuable. Although EVs do not contribute to higher sLRP1 levels in IDCM, a comprehensive analysis of EV content would provide further insights into the search for novel blood markers.

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Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis

Cited by 35 publications

References 69 publications

Verification and characterization of an alternative low density lipoprotein receptor-related protein 1 splice variant

Verification and characterization of an alternative low density lipoprotein receptor-related protein 1 splice variant

Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

Extracellular vesicles do not contribute to higher circulating levels of soluble LRP1 in idiopathic dilated cardiomyopathy

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