PMID- 29378845
OWN - NLM
STAT- MEDLINE
DCOM- 20190408
LR  - 20221017
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 13
DP  - 2018 Mar 30
TI  - Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving 
      mitochondrial function and suppressing endoplasmic reticulum stress.
PG  - 4735-4751
LID - S0021-9258(20)39777-5 [pii]
LID - 10.1074/jbc.M117.805069 [doi]
AB  - Estrogen receptor alpha (ERalpha) action plays an important role in pancreatic beta-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 ERalpha remain unclear. Because ERalpha regulates mitochondrial 
      metabolism in other cell types, we hypothesized that ERalpha may act to preserve 
      insulin secretion and promote beta-cell survival by regulating 
      mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this 
      hypothesis using pancreatic islet-specific ERalpha knockout (PERalphaKO) mice and Min6 
      beta-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 ERalpha replete Min6 beta-cells. 
      Increased expression of Oma1 and Chop was paralleled by increased oxygen 
      consumption and apoptosis susceptibility in ERalpha-KD cells. In contrast, ERalpha 
      overexpression and ligand activation reduced both Chop and Oma1 expression, 
      likely by ERalpha binding to consensus estrogen-response element sites in the Oma1 
      and Chop promoters. Together, our findings suggest that ERalpha promotes beta-cell 
      survival and insulin secretion through maintenance of mitochondrial 
      fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and 
      Chop repression.
FAU - Zhou, Zhenqi
AU  - Zhou Z
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Ribas, Vicent
AU  - Ribas V
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Rajbhandari, Prashant
AU  - Rajbhandari P
AD  - Department of Pathology and Laboratory Medicine and the Howard Hughes Research 
      Institute, Los Angeles, California 90095.
FAU - Drew, Brian G
AU  - Drew BG
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Moore, Timothy M
AU  - Moore TM
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Fluitt, Amy H
AU  - Fluitt AH
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Reddish, Britany R
AU  - Reddish BR
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Whitney, Kate A
AU  - Whitney KA
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Georgia, Senta
AU  - Georgia S
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Vergnes, Laurent
AU  - Vergnes L
AD  - Departments of Human Genetics, Los Angeles, California 90095.
FAU - Reue, Karen
AU  - Reue K
AD  - Departments of Human Genetics, Los Angeles, California 90095.
FAU - Liesa, Marc
AU  - Liesa M
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - Shirihai, Orian
AU  - Shirihai O
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095.
FAU - van der Bliek, Alexander M
AU  - van der Bliek AM
AD  - Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, 
      California 90095.
FAU - Chi, Nai-Wen
AU  - Chi NW
AD  - Department of Medicine, University of California, San Diego, La Jolla, California 
      92037.
FAU - Mahata, Sushil K
AU  - Mahata SK
AD  - Department of Medicine, University of California, San Diego, La Jolla, California 
      92037; Veterans Affairs San Diego Healthcare System, San Diego, California 92161.
FAU - Tiano, Joseph P
AU  - Tiano JP
AD  - Department of Medicine and Pharmacology, Tulane University Health Sciences 
      Center, New Orleans, Louisiana 70112.
FAU - Hewitt, Sylvia C
AU  - Hewitt SC
AD  - Receptor Biology Section, NIEHS, National Institutes of Health, Research Triangle 
      Park, North Carolina 27709.
FAU - Tontonoz, Peter
AU  - Tontonoz P
AD  - Department of Pathology and Laboratory Medicine and the Howard Hughes Research 
      Institute, Los Angeles, California 90095.
FAU - Korach, Kenneth S
AU  - Korach KS
AD  - Receptor Biology Section, NIEHS, National Institutes of Health, Research Triangle 
      Park, North Carolina 27709.
FAU - Mauvais-Jarvis, Franck
AU  - Mauvais-Jarvis F
AD  - Department of Medicine and Pharmacology, Tulane University Health Sciences 
      Center, New Orleans, Louisiana 70112.
FAU - Hevener, Andrea L
AU  - Hevener AL
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los 
      Angeles, California 90095; Iris Cantor UCLA Women's Health Research Center, Los 
      Angeles, California 90095. Electronic address: ahevener@mednet.ucla.edu.
LA  - eng
GR  - UL1 TR000124/TR/NCATS NIH HHS/United States
GR  - I01 BX003725/BX/BLRD VA/United States
GR  - R01 DK074970/DK/NIDDK NIH HHS/United States
GR  - U54 GM104940/GM/NIGMS NIH HHS/United States
GR  - K01 DK060484/DK/NIDDK NIH HHS/United States
GR  - R01 DK089109/DK/NIDDK NIH HHS/United States
GR  - U01 GM109764/GM/NIGMS NIH HHS/United States
GR  - R01 DK107444/DK/NIDDK NIH HHS/United States
GR  - P01 HL028481/HL/NHLBI NIH HHS/United States
GR  - F31 DK108657/DK/NIDDK NIH HHS/United States
GR  - P30 DK063491/DK/NIDDK NIH HHS/United States
GR  - R01 DK099618/DK/NIDDK NIH HHS/United States
GR  - U24 DK097748/DK/NIDDK NIH HHS/United States
GR  - R01 DK109724/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180129
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ddit3 protein, mouse)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Insulin)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 3.4.- (Metalloproteases)
RN  - EC 3.4.- (OMA1 protein, mouse)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Cell Survival
MH  - *Endoplasmic Reticulum Stress
MH  - Estrogen Receptor alpha/genetics/*metabolism
MH  - Female
MH  - Insulin/genetics/metabolism
MH  - Insulin-Secreting Cells/*metabolism
MH  - Metalloproteases/biosynthesis/genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/genetics/*metabolism
MH  - Mitochondrial Proteins/biosynthesis/genetics
MH  - *Mitophagy
MH  - Reactive Oxygen Species/metabolism
MH  - Transcription Factor CHOP/biosynthesis/genetics
PMC - PMC5880140
OTO - NOTNLM
OT  - apoptosis
OT  - endoplasmic reticulum stress (ER stress)
OT  - estrogen action
OT  - estrogen receptor
OT  - insulin secretion
OT  - mitochondrial dynamics
OT  - mitochondrial metabolism
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/01/31 06:00
MHDA- 2019/04/09 06:00
PMCR- 2019/03/30
CRDT- 2018/01/31 06:00
PHST- 2017/07/28 00:00 [received]
PHST- 2017/11/24 00:00 [revised]
PHST- 2018/01/31 06:00 [pubmed]
PHST- 2019/04/09 06:00 [medline]
PHST- 2018/01/31 06:00 [entrez]
PHST- 2019/03/30 00:00 [pmc-release]
AID - S0021-9258(20)39777-5 [pii]
AID - M117.805069 [pii]
AID - 10.1074/jbc.M117.805069 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Mar 30;293(13):4735-4751. doi: 10.1074/jbc.M117.805069. Epub 
      2018 Jan 29.