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

Sjölander, Jonatan LU ; Byman, Elin LU ; Kulak, Klaudia LU ; Nilsson, Sara C. LU ; Zhang, Enming LU ; Krus, Ulrika LU ; Westermark, Gunilla T.; Storm, Petter LU ; King, Ben C. LU and Renström, Erik LU , et al. (2016) In Journal of Biological Chemistry 291(41). p.21644-21655
Abstract

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... (More)

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.

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Journal of Biological Chemistry
volume
291
issue
41
pages
12 pages
publisher
ASBMB
external identifiers
  • scopus:84990188655
  • wos:000385999200030
ISSN
0021-9258
DOI
10.1074/jbc.M116.731141
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English
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yes
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dde96a73-77d3-4457-bc8d-c81f34da3f69
date added to LUP
2016-10-21 07:14:55
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2017-10-01 05:24:45
@article{dde96a73-77d3-4457-bc8d-c81f34da3f69,
  abstract     = {<p>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.</p>},
  author       = {Sjölander, Jonatan and Byman, Elin and Kulak, Klaudia and Nilsson, Sara C. and Zhang, Enming and Krus, Ulrika and Westermark, Gunilla T. and Storm, Petter and King, Ben C. and Renström, Erik and Blom, Anna M.},
  issn         = {0021-9258},
  language     = {eng},
  month        = {10},
  number       = {41},
  pages        = {21644--21655},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {C4b-binding protein protects β-cells from islet amyloid polypeptide-induced cytotoxicity},
  url          = {http://dx.doi.org/10.1074/jbc.M116.731141},
  volume       = {291},
  year         = {2016},
}