@article{1687c3ac907f4879a862e8458f105578,
title = "Estrogen receptor protects pancreatic -cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress",
abstract = "Estrogen receptor (ER) action plays an important role in pancreatic -cell function and survival; thus, it is considered a potential therapeutic target for the treatment of type 2 diabetes in women. However, the mechanisms underlying the protective effects of ER remain unclear. Because ER regulates mitochondrial metabolism in other cell types, we hypothesized that ER may act to preserve insulin secretion and promote -cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ER knockout (PERKO) mice and Min6 -cells in culture with Esr1 knockdown (KD). We found that Esr1-KD promoted reactive oxygen species production that associated with reduced fission/fusion dynamics and impaired mitophagy. Electron microscopy showed mitochondrial enlargement and a pro-fusion phenotype. Mitochondrial cristae and endoplasmic reticulum were dilated in Esr1-KD compared with ER replete Min6 -cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ER-KD cells. In contrast, ER overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ER binding to consensus estrogen-response element sites in the Oma1 and Chop promoters. Together, our findings suggest that ER promotes -cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and Chop repression.",
author = "Zhenqi Zhou and Vicent Ribas and Prashant Rajbhandari and Drew, {Brian G.} and Moore, {Timothy M.} and Fluitt, {Amy H.} and Reddish, {Britany R.} and Whitney, {Kate A.} and Senta Georgia and Laurent Vergnes and Karen Reue and Marc Liesa and Orian Shirihai and {Van Der Bliek}, {Alexander M.} and Chi, {Nai Wen} and Mahata, {Sushil K.} and Tiano, {Joseph P.} and Hewitt, {Sylvia C.} and Peter Tontonoz and Korach, {Kenneth S.} and Franck Mauvais-Jarvis and Hevener, {Andrea L.}",
note = "Funding Information: This work was supported in part by the UCLA Department of Medicine, the UCLA Iris Cantor Women's Health Foundation, UCLA CTSI Grant ULTR000124, the UCLA Claude D. Pepper Older Americans Independence Center, UCSD-UCLA Diabetes Research Center, and National Institutes of Health Grants DK060484, DK109724, and P30DK063491, and NURSA NDSP U24DK097748 (to A. L. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: 2 Supported by National Institutes of Health Grant R01 DK074970. Funding Information: This work was supported in part by the UCLA Department of Medicine, the UCLA Iris Cantor Women{\textquoteright}s Health Foundation, UCLA CTSI Grant ULTR000124, the UCLA Claude D. Pepper Older Americans Independence Center, UCSD-UCLA Diabetes Research Center, and National Institutes of Health Grants DK060484, DK109724, and P30DK063491, and NURSA NDSP U24DK097748 (to A. L. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2018 American Society for Biochemistry and Molecular Biology Inc. All Rights Reserved.",
year = "2018",
month = mar,
day = "30",
doi = "10.1074/jbc.M117.805069",
language = "English",
volume = "293",
pages = "4735--4751",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "13",
}
