Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis

Oskarsson, Marie E. (författare): Uppsala universitet,Institutionen för medicinsk cellbiologi

Singh, Kailash (författare): Uppsala universitet,Institutionen för medicinsk cellbiologi

Wang, Jian (författare): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi

Vlodavsky, Israel (författare)

Li, Jin-ping (författare): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi

Westermark, Gunilla T. (författare): Uppsala universitet,Institutionen för medicinsk cellbiologi

(creator_code:org_t)

2015
2015
Engelska.
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 290:24, s. 15121-15132

Relaterad länk:: https://urn.kb.se/re...; visa fler...; https://doi.org/10.1...; visa färre...

Abstract Ämnesord

Stäng

Deposition of beta cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mM glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that beta cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of beta cells.

Av författaren/redakt...: Oskarsson, Marie ...; Singh, Kailash; Wang, Jian; Vlodavsky, Israe ...; Li, Jin-ping; Westermark, Guni ...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinsk biotek ...; och Medicinsk biotek ...

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