Glucolipotoxicity initiates pancreatic β-cell death through 1 tumour necrosis factor receptor 5 (TNFR5 / CD40) mediated 2 STAT1 and NF-κB activation

Bagnati, M., Ogunkolade, B.W., Marshall, C., Tucci, C., Hanna, K., Jones, T.A., Bugliani, M., Nedjai, B., Caton, P.W., Kieswich, J., Yaqoob, M.M., Ball, G.R. ORCID: 0000-0001-5828-7129, Marchetti, P., Hitman, G.A. and Turner, M.D. ORCID: 0000-0001-7175-1053, 2016. Glucolipotoxicity initiates pancreatic β-cell death through 1 tumour necrosis factor receptor 5 (TNFR5 / CD40) mediated 2 STAT1 and NF-κB activation. Cell Death and Disease, 7, e2329. ISSN 2041-4889

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Abstract

Type 2 diabetes is a chronic metabolic disorder where failure to maintain normal glucose homeostasis is associated with, and exacerbated by, obesity and the concomitant elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in insulin-producing β-cell mass through activation of the transcription factors NF-κB and STAT1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the 40 mechanism(s) by which glucolipotoxicity initially induces NF-κB and ST AT1 activation is currently poorly defined. Using high density microarray analysis of the β-cell transcritptome we have identified those genes and proteins most sensitive to glucose and fatty acid environment. Our data shows that of those potentially able to activate STAT1 or NF-κB pathways, TNFR5 is the most highly upregulated by glucolipotoxicity. Importantly our data also shows that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knock -down of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicates for the first time that TNFR5 signalling plays a major role in triggering glucolipotoxic islet cell death.

Item Type:	Journal article
Alternative Title:	TNFR5 / CD40 signalling in islet cell death [running title]
Publication Title:	Cell Death and Disease
Creators:	Bagnati, M., Ogunkolade, B.W., Marshall, C., Tucci, C., Hanna, K., Jones, T.A., Bugliani, M., Nedjai, B., Caton, P.W., Kieswich, J., Yaqoob, M.M., Ball, G.R., Marchetti, P., Hitman, G.A. and Turner, M.D.
Publisher:	Nature Publishing Group
Date:	11 August 2016
Volume:	7
ISSN:	2041-4889
Identifiers:	Number Type 10.1038/cddis.2016.203 DOI
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	27 Jul 2016 07:41
Last Modified:	10 Oct 2017 12:58
URI:	https://irep.ntu.ac.uk/id/eprint/28213

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