Résumés disponibles (91) :

RABHI Nabil (UMR CNRS 8199 éq. 02 - Jean-Sebastien ANNICOTTE)
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@mail :  nabil14006@gmail.com      tél. :  03 20 97 42 59

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Titre de la communication :
The P300/CBP-associated factor (PCAF) links ER stress to β-cell function and insulin secretion
Auteurs (et leurs adresses) de la communication :
Nabil Rabhi1, Pierre-Damien Denechaud2, Elisabet Salas1, Amélie Bonnefond1, Carine De Bettignies1, Philippe Froguel1 and Jean-Sébastien Annicotte1 1EGID, CNRS UMR 8199, Lille 2 University, Lille, France ; 2Université de Lausanne, Lausanne, Suisse
Résumé de la communication :
Pancreatic β-cells control insulin secretion through a fine-tuned process. Dysfunctions of this particular cell type are at the origin of pathological conditions, such as Diabetes. However the mechanism leading β-cell failure is poorly understood. The lysine/histone acetyl transferase PCAF has been demonstrated to regulate several β cells enriched transcription factors, such as E2F1, PDX-1, HNF1, MafA. Moreover, PCAF modulates the acetylation of the insulin promoter, suggesting potential role in the control of metabolic pathways and related diseases. However, the in vivo functions of PCAF and its contribution to diabetes physiopathology are unknown. In an attempt to decipher PCAF functions in the β-cell, we analysed the PCAF interactome in the β-cell line Min6. We observed that PCAF interact physically with protein involved in the folding of insulin, as well as in the unfolded protein response (UPR). Since UPR has been associated with β-cell failure and diabetes, we evaluated the effect of Pcaf gene inactivation in mice. We showed that Pcaf-/- mice are hyperglycemic in fed conditions and are resistant to diet-induced obesity. Moreover, these mice are glucose-intolerant under chow or high-fat diet due to decreased insulin secretion. Using isolated islets, we further confirmed that Pcaf-/- β-cells were unable to secrete insulin in response to glucose. Electron microscopy analysis of Pcaf -/- mice isolated islets showed defects in insulin folding, maturation and/or crystalization process, suggesting that PCAF could play a key role in the UPR. In accordance with these observations, mRNA levels of key genes involved in UPR were downregulated in Pcaf-/- isolated islets. Finally, mRNA levels of Pcaf were decreased in human diabetic islets when compared to control patients. In summary we provide evidence that the PCAF is involved in glucose homeostasis through its role on insulin folding and ER stress response, and could play a key role in the development of type 2 diabetes.

RABHI Nabil (UMR CNRS 8199 éq. 02 - Jean-Sebastien ANNICOTTE)