Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation

Marta Bagnati; Babatunji W Ogunkolade; Catriona Marshal; Carmen Tucci; Katie Hanna; Tania A Jones; Marco Bugliani; Belinda Nedjai; Paul W Caton; Julius Kieswich; Muhammed M Yaqoob; Graham R Ball; Piero Marchetti; Graham A Hitman; Mark D Turner

doi:10.1038/cddis.2016.203

Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation

Marta Bagnati, Babatunji W Ogunkolade, Catriona Marshal, Carmen Tucci, Katie Hanna, Tania A Jones, Marco Bugliani, Belinda Nedjai, Paul W Caton, Julius Kieswich, Muhammed M Yaqoob, Graham R Ball, Piero Marchetti, Graham A Hitman, Mark D Turner

Nutritional Sciences

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Abstract

Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis 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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 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 show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.

Original language	English
Article number	e2329
Journal	Cell Death and Disease
Early online date	11 Aug 2016
DOIs	https://doi.org/10.1038/cddis.2016.203
Publication status	E-pub ahead of print - 11 Aug 2016

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Glucolipotoxicity initiates pancreatic_BAGNATI_Accepted 26May2016_GOLD VoRFinal published version, 1.44 MBLicence: CC BY

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Bagnati, M., Ogunkolade, B. W., Marshal, 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., & Turner, M. D. (2016). Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation. Cell Death and Disease, Article e2329. Advance online publication. https://doi.org/10.1038/cddis.2016.203

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title = "Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation",

abstract = "Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis 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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 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 show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.",

author = "Marta Bagnati and Ogunkolade, {Babatunji W} and Catriona Marshal and Carmen Tucci and Katie Hanna and Jones, {Tania A} and Marco Bugliani and Belinda Nedjai and Caton, {Paul W} and Julius Kieswich and Yaqoob, {Muhammed M} and Ball, {Graham R} and Piero Marchetti and Hitman, {Graham A} and Turner, {Mark D}",

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AU - Ogunkolade, Babatunji W

AU - Marshal, Catriona

AU - Tucci, Carmen

AU - Hanna, Katie

AU - Jones, Tania A

AU - Bugliani, Marco

AU - Nedjai, Belinda

AU - Caton, Paul W

AU - Kieswich, Julius

AU - Yaqoob, Muhammed M

AU - Ball, Graham R

AU - Marchetti, Piero

AU - Hitman, Graham A

AU - Turner, Mark D

PY - 2016/8/11

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N2 - Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis 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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 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 show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.

AB - Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis 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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 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 show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.

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DO - 10.1038/cddis.2016.203

M3 - Article

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JF - Cell Death and Disease

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ER -

Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation

Abstract

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