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C4b-binding protein protects β-cells from islet amyloid polypeptide-induced cytotoxicity

Author:
  • Jonatan Sjölander
  • Elin Byman
  • Klaudia Kulak
  • Sara C. Nilsson
  • Enming Zhang
  • Ulrika Krus
  • Gunilla T. Westermark
  • Petter Storm
  • Ben C. King
  • Erik Renström
  • Anna M. Blom
Publishing year: 2016-10-07
Language: English
Pages: 21644-21655
Publication/Series: Journal of Biological Chemistry
Volume: 291
Issue: 41
Document type: Journal article
Publisher: ASBMB

Abstract english

C4BP (C4b-binding protein) is a polymer of seven identical α chains and one unique β chain synthesized in liver and pancreas. We showed previously that C4BP enhances islet amyloid polypeptide (IAPP) fibril formation in vitro. Now we report that polymeric C4BP strongly inhibited lysis of human erythrocytes incubated with monomeric IAPP, whereas no lysis was observed after incubation with preformed IAPP fibrils. In contrast, incubation with the monomeric α-chain of C4BP was less effective. These data indicate that polymeric C4BP with multiple binding sites for IAPP neutralizes lytic activity of IAPP. Furthermore, addition of monomeric IAPP to a rat insulinoma cell line (INS-1) resulted in decreased cell viability, which was restored in the presence of physiological concentrations of C4BP. Treatment of INS-1 cells and primary rat islets with IAPP also diminished their ability to secrete insulin upon stimulation with glucose, which was reversed in the presence of C4BP. Further, C4BP was internalized together with IAPP into INS-1 cells. Pathway analyses of mRNA expression microarray data indicated that cells exposed to C4BP and IAPP in comparison with IAPP alone increased expression of genes involved in cholesterol synthesis. Depletion of cholesterol through methyl-β-cyclodextrin or cholesterol oxidase abolished the protective effect of C4BP on IAPP cytotoxicity of INS-1 cells. Also, inhibition of phosphoinositide 3-kinase but not NF-κB had a similar effect. Taken together, C4BP protects β-cells from IAPP cytotoxicity by modulating IAPP fibril formation extracellularly and also, after uptake by the cells, by enhancing cholesterol synthesis.

Keywords

  • Cell and Molecular Biology

Other

Published
  • Protein Chemistry, Malmö
  • Clinical Memory Research
  • Islet patophysiology
  • Diabetes and Endocrinology
  • ISSN: 0021-9258
Erik Renström
E-mail: erik [dot] renstrom [at] med [dot] lu [dot] se

Deputy head of department

Department of Clinical Sciences, Malmö

+46 40 39 11 57

+46 40 39 11 57

Principal investigator

Islet patophysiology

+46 40 39 11 57

+46 40 39 11 57

20-3-308

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00