Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin–proteasome system in pancreatic beta cell dysfunction

Bugliani, Marco; Liechti, Robin; Cheon, Hwanju; Suleiman, Mara; Marselli, Lorella; Kirkpatrick, Clare L.; Filipponi, Franco; Boggi, Ugo; Xenarios, Ioannis; Syed, Farooq; Ladrière, Laurence; Wollheim, Claes; Lee, Myung-Shik M.-S.; Marchetti, Piero

doi:10.1016/j.mce.2012.12.001

Cited by 77 publications

(82 citation statements)

References 68 publications

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“…However, HSPA1A and HSPA6, the two specific isoforms investigated in our study, were not differentially expressed. Bugliani et al studied the transcriptome of pancreatic islets from individuals with type 2 diabetes and demonstrated downregulation of several de-ubiquitinating enzymes of the USP family [31]. Finally, genome-wide association studies have linked the homeodomain transcription factor haematopoietically expressed homeobox (HHEX) to type 2 diabetes, and variations within the HHEX gene are associated with decreased insulin secretion [32].…”

Section: Discussionmentioning

confidence: 99%

HSF1 acetylation decreases its transcriptional activity and enhances glucolipotoxicity-induced apoptosis in rat and human beta cells

et al. 2017

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Aims/hypothesis Heat shock factor protein 1 (HSF1) is a transcription factor that regulates the expression of key molecular chaperones, thereby orchestrating the cellular response to stress. This system was recently implicated in the control of insulin sensitivity and is therefore being scrutinised as a novel therapeutic avenue for type 2 diabetes. However, the regulation and biological actions of HSF1 in beta cells remain elusive. Herein, we sought to investigate the regulation of HSF1 in pancreatic beta cells and to study its potential role in cell survival. Methods We exposed human islets and beta cell lines to glucolipotoxicity and thapsigargin. HSF1 activity was evaluated by gel shift assay. HSF1 acetylation and interaction with the protein acetylase cAMP response element binding protein (CBP) were investigated by western blot. We measured the expression of HSF1 and its canonical targets in islets from Goto-Kakizaki (GK) rat models of diabetes and delineated the effects of HSF1 acetylation using mutants mimicking constitutive acetylation and deacetylation of the protein.Results Glucolipotoxicity promoted HSF1 acetylation and interaction with CBP. Glucolipotoxicity-induced HSF1 acetylation inhibited HSF1 DNA binding activity and decreased the expression of its target genes. Restoration of HSF1 activity in beta cells prevented glucolipotoxicity-induced endoplasmic reticulum stress and apoptosis. However, overexpression of a mutant protein (K80Q) mimicking constitutive acetylation of HSF1 failed to confer protection against glucolipotoxicity. Finally, we showed that expression of HSF1 and its target genes were altered in islets from diabetic GK rats, suggesting that this pathway could participate in the pathophysiology of diabetes and constitutes a potential site for therapeutic intervention. Conclusions/interpretation Our results unravel a new mechanism by which HSF1 inhibition is required for glucolipotoxicityinduced beta cell apoptosis. Restoring HSF1 activity may represent a novel strategy for the maintenance of a functional beta cell mass. Our study supports the therapeutic potential of HSF1/heat shock protein-targeting agents in diabetes treatment.

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Section: Discussionmentioning

confidence: 99%

HSF1 acetylation decreases its transcriptional activity and enhances glucolipotoxicity-induced apoptosis in rat and human beta cells

et al. 2017

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“…Ubiquitination, a process in the ubiquitin-proteasome system, is responsible for the majority of protein degradation in the intracellular pathway of mammalian cells (Ponsuksili et al, 2009;Keller et al, 2012;Bugliani et al, 2013). Three enzymatic components, designated as E1 (activation enzyme), E2 (conjugate enzyme), and E3 (ligase enzyme), promote the conjugation of ubiquitin molecules to the target proteins (Keller et al, 2012;Bugliani et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Three enzymatic components, designated as E1 (activation enzyme), E2 (conjugate enzyme), and E3 (ligase enzyme), promote the conjugation of ubiquitin molecules to the target proteins (Keller et al, 2012;Bugliani et al, 2013). The ubiquitin-proteasome named 26S proteasome is a large multicatalytic protease complex that degrades ubiquitinated proteins to small peptides (Keller et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Effect of UBE3C polymorphisms on intramuscular fat content and fatty acid composition in Duroc pigs

Supakankul

Mekchay

2016

Genet. Mol. Res.

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ABSTRACT. Ubiquitin protein ligase E3C (UBE3C) is involved in the ubiquitin-proteasome pathway, and several ubiquitin protein ligases are important for fat deposition and lipid metabolism. The objective of this study was to analyze the association between a single nucleotide polymorphism (SNP) of the UBE3C gene with intramuscular fat (IMF) content and fatty acid (FA) composition in Duroc pigs. Four SNP markers (g.1586399A>G, g.1591358G>A, g.1600132G>C, and g.1600166G>A) of porcine UBE3C were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method, and their associations with IMF content and FA composition were investigated in a commercial Duroc pig population. Two SNP markers (g.1586399A>G and g.1591358G>A) were segregated among the pigs. No UBE3C polymorphisms at g.1600132G>C or g.1600166G>A were observed. The UBE3C g.1586399A>G SNP was significantly associated with IMF content, while the UBE3C g.1591358G>A SNP was associated with palmitic, stearic, eicosenoic, and eicosadienoic acid levels, and saturated FA levels. These results suggest that polymorphisms in porcine UBE3C are correlated with IMF content and FA composition, and confirm the importance of porcine UBE3C as a candidate gene for fat deposition in pigs.

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“…A later report described microarray results obtained with islets prepared from six type 2 diabetic and seven non-diabetic organ donors. These revealed the upregulation of the expression a few cytokines (IL-19, IL-25, CSF1, LTA and IFNB1) and chemokines (CCL5, CCL7, CCL13, CCL16, CCL21, CCL25 and CX3CL1) known to be involved in inflammatory and/or immunomodulatory mechanisms in the diabetic samples [30]. More recently, microarray data were generated by Taneera et al [31] using islets from nine type 2 diabetic individuals and 54 non-diabetic controls.…”

Section: Islet Expression Of Cytokines and Chemokines In Type 2 Diabetesmentioning

confidence: 99%

Islet inflammation in type 2 diabetes

Marchetti

2016

Diabetologia

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Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin–proteasome system in pancreatic beta cell dysfunction

Cited by 77 publications

References 68 publications

HSF1 acetylation decreases its transcriptional activity and enhances glucolipotoxicity-induced apoptosis in rat and human beta cells

HSF1 acetylation decreases its transcriptional activity and enhances glucolipotoxicity-induced apoptosis in rat and human beta cells

Effect of UBE3C polymorphisms on intramuscular fat content and fatty acid composition in Duroc pigs

Islet inflammation in type 2 diabetes

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