| Autor: |
Dahlby T; Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Simon C; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark., Backe MB; Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Dahllöf MS; Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Holson E; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Wagner BK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Böni-Schnetzler M; Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Marzec MT; Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Lundh M; Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Mandrup-Poulsen T; Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark. |
| Abstrakt: |
Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor. |
