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Cell Rep. 2016 May 3;15(5):1051-1061. doi: 10.1016/j.celrep.2016.03.079. Epub 2016 Apr 21.

KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response.

Author information

1
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
2
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
3
Laboratory for Integrative and Systems Physiology, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland.
4
Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, 34298 Montpellier, France.
5
University Lille, INSERM, CHU Lille, U1190 - EGID, 59000 Lille, France.
6
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France; Departments of Genomics and Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Electronic address: p.froguel@imperial.ac.uk.
7
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France. Electronic address: jean-sebastien.annicotte@inserm.fr.

Abstract

The endoplasmic reticulum (ER) unfolded protein response (UPR(er)) pathway plays an important role in helping pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPR(er) gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germline and β cell-specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance. Genome-wide analysis of Kat2b-regulated genes and functional assays reveal a critical role for Kat2b in maintaining UPR(er) gene expression and subsequent β cell function. Importantly, Kat2b expression is decreased in mouse and human diabetic β cells and correlates with UPR(er) gene expression in normal human islets. In conclusion, Kat2b is a crucial transcriptional regulator for adaptive β cell function during metabolic stress by controlling UPR(er) and represents a promising target for T2D prevention and treatment.

PMID:
27117420
DOI:
10.1016/j.celrep.2016.03.079
[Indexed for MEDLINE]
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