| Title |
HSF1 acetylation decreases its transcriptional activity and enhances glucolipotoxicity-induced apoptosis in rat and human beta cells
|
|---|---|
| Published in |
Diabetologia, May 2017
|
| DOI | 10.1007/s00125-017-4310-7 |
| Pubmed ID | |
| Authors |
Indri Purwana, Jun J. Liu, Bernard Portha, Jean Buteau |
| Abstract |
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. 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. 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. Our results unravel a new mechanism by which HSF1 inhibition is required for glucolipotoxicity-induced 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. |
X Demographics
The data shown below were collected from the profiles of 18 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Canada | 5 | 28% |
| United Kingdom | 4 | 22% |
| Germany | 1 | 6% |
| Cabo Verde | 1 | 6% |
| Unknown | 7 | 39% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 12 | 67% |
| Scientists | 5 | 28% |
| Practitioners (doctors, other healthcare professionals) | 1 | 6% |
Mendeley readers
The data shown below were compiled from readership statistics for 33 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 33 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 6 | 18% |
| Student > Bachelor | 4 | 12% |
| Student > Doctoral Student | 3 | 9% |
| Other | 3 | 9% |
| Student > Ph. D. Student | 3 | 9% |
| Other | 6 | 18% |
| Unknown | 8 | 24% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 7 | 21% |
| Medicine and Dentistry | 4 | 12% |
| Pharmacology, Toxicology and Pharmaceutical Science | 3 | 9% |
| Business, Management and Accounting | 1 | 3% |
| Agricultural and Biological Sciences | 1 | 3% |
| Other | 6 | 18% |
| Unknown | 11 | 33% |
Attention Score in Context
This research output has an Altmetric Attention Score of 10. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 November 2020.
All research outputs
#3,263,804
of 22,974,684 outputs
Outputs from Diabetologia
#1,536
of 5,083 outputs
Outputs of similar age
#62,062
of 313,664 outputs
Outputs of similar age from Diabetologia
#33
of 62 outputs
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