Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function

Ramin‐Mangata, Stéphane; Thedrez, Aurélie; Nativel, Brice; Diotel, Nicolas; Blanchard, Valentin; Wargny, Matthieu; Aguesse, Audrey; Billon-Crossouard, Stéphanie; Vindis, Cécile; May, Cédric Le; Hulin, Philippe; Armanet, Mathieu; Gmyr, Valéry; Pattou, François; Croyal, Mikaël; Meilhac, Olivier; Nobécourt, Estelle; Cariou, Bertrand; Lambert, Gilles

doi:10.1016/j.atherosclerosis.2021.03.044

Cited by 19 publications

(25 citation statements)

References 49 publications

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“…Our data is consistent with observations in mouse islets [31]. The reasons for the discrepancy with Ramin-Mangata et al [32] are difficult to discuss, as this study presents FACS data in arbitrary units without supporting FACS plots. Taken together, we propose that in pancreatic beta cells, LDLR and VLDLR levels are regulated by PCSK9 extracellularly rather than through intracellular degradation.…”

Section: Discussionsupporting

confidence: 86%

“…It is for example the case for PDX1 and NKX6-1 that are known to play major roles in beta cell development and function [55][56][57]. We also detected some perturbation in glucose-stimulated insulin secretion with a specific increase in basal insulin secretion, which was not addressed by Ramin-Mangata et al [32]. Taken together, the phenotype observed upon PCSK9 knockdown (decreased expression of specific transcription factors and increased basal insulin secretion) resembles that observed in immature fetal beta cells [58,59] and in insulin-producing beta cells differentiated in vitro from multipotent stem cells [60,61].…”

Section: Discussionmentioning

confidence: 55%

“…In mouse islets, loss of beta-cell PCSK9 results in unchanged LDLR protein levels [31]. Unexpectedly, data from a recently published study [32] indicate that PCSK9 knockdown in EndoC-H1 cells increased LDLR cell surface expression by 20%. Our data do not support this last claim.…”

Section: Discussionmentioning

confidence: 99%

“…However, the precise cell type expressing PCSK9 within islets remains unclear. Some studies demonstrate that PCSK9 is only expressed in somatostatin-producing delta cells [28,30], while other studies indicate that beta cells express PCSK9 [29,31,32]. The function of PCSK9 within islets is also debated.…”

Section: Introductionmentioning

confidence: 99%

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PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

Saitoski

Ryaboshapkina

Hamza

et al. 2021

Preprint

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Aims/hypothesis: Proprotein convertase subtilisin/kexin 9 (PCSK9) is involved in the degradation of LDLR. However, PCSK9 can target other proteins in a cell-type specific manner. While PCSK9 has been detected in pancreatic islets, its expression in insulin-producing pancreatic beta cells is debated. Herein, we studied PCSK9 expression, regulation and function in the human pancreatic beta cell line EndoC-βH1. Methods: We assessed PCSK9 expression in mouse and human pancreatic islets, and in the pancreatic beta cell line EndoC-βH1. We also studied PCSK9 regulation by cholesterol, lipoproteins, Mevastatin, and by SREBPs transcription factors. To evaluate PCSK9 function in pancreatic beta cells, we performed PCSK9 gain-and loss-of-function experiments in EndoC-βH1 using siPCSK9 or recombinant PCSK9 treatments, respectively. Results: We demonstrate that PCSK9 is expressed and secreted by pancreatic beta cells. In EndoC-βH1 cells, PCSK9 expression is regulated by cholesterol and by SREBPs transcription factors. Importantly, PCSK9 knockdown results in multiple transcriptome, proteome and secretome deregulations and impaired insulin secretion. By gain- and loss-of- function experiments, we observed that PCSK9 regulates the expression levels of LDLR and VLDLR through an extracellular mechanism while CD36, PD-L1 and HLA-ABC are regulated through an intracellular mechanism. Conclusions/interpretation: Collectively, these results highlight PCSK9 as an important regulator of CD36, PD-L1 and HLA-ABC cell surface expression in pancreatic beta cells. Data availability: RNA-seq data have been deposited to GEO database with accession number GSE182016. Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the following identifiers: PXD027921, PXD027911 and PXD027913.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

Saitoski

Ryaboshapkina

Hamza

et al. 2021

Preprint

Self Cite

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“…Undoubtedly, new technologies may fuel cheaper and long-lasting PCSK9 inhibitors that would then be more widely prescribed in clinics worldwide. While the physiological functions of PCSK9 in tissues other than liver ( 143 , 144 ), such as small intestine ( 145 , 146 ) and pancreatic β-cells ( 47 , 147 ), are starting to be defined, those in kidney, thymus, brain, and testis ( 41 ) still require more investigations. Tissue-specific PCSK9 KO in mouse small intestine ( 146 ), pancreatic β-cells ( 47 ), and lung epithelia ( 128 ) allowed some dissection of the relationship between the autocrine and endocrine functions of PCSK9 but clearly emphasized the dominant role of circulating PCSK9 originating from liver ( 48 , 80 ).…”

Section: Discussionmentioning

confidence: 99%

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

Seidah

2021

Journal of Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Carugo

Sirtori

Corsini

et al. 2022

Curr Atheroscler Rep

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Purpose of Review Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD). Recent Findings While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Summary Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

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Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function

Cited by 19 publications

References 49 publications

PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

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