title: C4b-binding Protein Protects β-Cells from Islet Amyloid Polypeptide-induced Cytotoxicity.
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 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.
authors: From the Departments of Translational Medicine and.
authors: Jonatan
authors: J
authors: Sjölander
authors: From the Departments of Translational Medicine and.
authors: Elin
authors: E
authors: Byman
authors: From the Departments of Translational Medicine and.
authors: Klaudia
authors: K
authors: Kulak
authors: From the Departments of Translational Medicine and.
authors: Sara C
authors: SC
authors: Nilsson
authors: Clinical Sciences, Lund University, S-20502 Malmö, Sweden and.
authors: Enming
authors: E
authors: Zhang
authors: Clinical Sciences, Lund University, S-20502 Malmö, Sweden and.
authors: Ulrika
authors: U
authors: Krus
authors: the Department of Medical Cell Biology, Uppsala University, S-75123 Uppsala, Sweden.
authors: Gunilla T
authors: GT
authors: Westermark
authors: Clinical Sciences, Lund University, S-20502 Malmö, Sweden and.
authors: Petter
authors: P
authors: Storm
authors: From the Departments of Translational Medicine and.
authors: Ben C
authors: BC
authors: King
authors: Clinical Sciences, Lund University, S-20502 Malmö, Sweden and.
authors: Erik
authors: E
authors: Renström
authors: From the Departments of Translational Medicine and anna.blom@med.lu.se.
authors: Anna M
authors: AM
authors: Blom
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis*; D002789:Cholesterol Oxidase / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000096:biosynthesis*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D050716:Complement C4b-Binding Protein; D058228:Islet Amyloid Polypeptide; D002784:Cholesterol; D002789:Cholesterol Oxidase; D019869:Phosphatidylinositol 3-Kinases
keywords: amyloid; beta cell (B-cell); cell death; cholesterol; complement system