PCSK9 is expressed in pancreatic δ-cells and does not alter insulin secretion

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Abstract

PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a proprotein convertase that plays a key role in cholesterol homeostasis by decreasing hepatic low-density lipoprotein receptor (LDLR) protein expression. Here, we investigated the expression and the function of PCSK9 in pancreatic islets. Immunohistochemistry analysis showed that PCSK9 co-localized specifically with somatostatin in human pancreatic δ-cells, with no expression in α- and β-cells. PCSK9 seems not to be secreted by mouse isolated islets maintained in culture. Pcsk9-deficiency led to a 200% increase in LDLR protein content in mouse isolated islets, mainly in β-cells. Conversely, incubation of islets with recombinant PCSK9 almost abolished LDLR expression. However, Pcsk9-deficiency did not alter cholesterol content nor glucose-stimulated insulin secretion in mouse islets. Finally, invivo glucose tolerance was similar in Pcsk9+/+ and Pcsk9−/− mice under basal conditions and following streptozotocin treatment. These results suggest, at least in mice, that PCSK9 does not alter insulin secretion.

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Material and methods

Hormone immunoassays. Insulin content and secretion were assessed in mice isolated islets by radioimmunoassay (Linco Research, St. Charles, Missouri, USA). Plasma insulin levels in mice were measured by ELISA (Crystal Chem Inc., Chicago, Illinois, USA). Secreted insulin and insulin content of human islets were assessed with an immunoradiometric assay (Bi-Insulin IRMA, SANOFI Diagnostics Pasteur, Marnes-la-Coquette, France). Somatostatin secretion of isolated islets was measured using an EIA kit

PCSK9 is expressed in human pancreatic δ-cells

First, we verified the expression of PCSK9 mRNA in isolated pancreatic islets from Pcsk9+/+ male mice. Real time Q-PCR analysis showed that the expression of PCSK9 in mouse isolated islets was about 30% of that detected in mouse liver (Fig. 1A). Next, we investigated the expression of PCSK9 in the human pancreas. While PCSK9 mRNA was detected in human islets from pancrease donors (n = 3), PCSK9 was not expressed in the human pancreatic carcinoma cell line Panc1 (Fig. 1B).

To further confirm the

Acknowledgments

This work was supported by Agence Nationale de la Recherche («Physiopathologies humaines 2006 R0651ONS»), Fondation de France, Fondation Cœur et Artères, and ALFEDIAM. C. Langhi is a recipient of a fellowship from the Nouvelle Société Française d’Athérosclérose. C. Le May was supported by a grant from the Fondation pour la Recherche Médicale. P. Costet and B. Cariou are titulars of a Contrat d’interface INSERM-CHU de Nantes. We acknowledge Dr. Philippe Lefebvre (INSERM U545) for providing us

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    These authors contributed equally to this work.

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