NDLI: Spontaneous Development of Endoplasmic Reticulum Stress That Can Lead to Diabetes Mellitus Is Associated with Higher Calcium-independent Phospholipase A2 Expression

Content Provider	PubMed Central
Author	Lei, Xiaoyong Zhang, Sheng Barbour, Suzanne E. Bohrer, Alan Ford, Eric L. Koizumi, Akio Papa, Feroz R. Ramanadham, Sasanka
Abstract	Our recent studies indicate that endoplasmic reticulum (ER) stress causes INS-1 cell apoptosis by a Ca2+-independent phospholipase A2 (iPLA2β)-mediated mechanism that promotes ceramide generation via sphingomyelin hydrolysis and subsequent activation of the intrinsic pathway. To elucidate the association between iPLA2β and ER stress, we compared β-cell lines generated from wild type (WT) and Akita mice. The Akita mouse is a spontaneous model of ER stress that develops hyperglycemia/diabetes due to ER stress-induced β-cell apoptosis. Consistent with a predisposition to developing ER stress, basal phosphorylated PERK and activated caspase-3 are higher in the Akita cells than WT cells. Interestingly, basal iPLA2β, mature SREBP-1 (mSREBP-1), phosphorylated Akt, and neutral sphingomyelinase (NSMase) are higher, relative abundances of sphingomyelins are lower, and mitochondrial membrane potential (ΔΨ) is compromised in Akita cells, in comparison with WT cells. Exposure to thapsigargin accelerates ΔΨ loss and apoptosis of Akita cells and is associated with increases in iPLA2β, mSREBP-1, and NSMase in both WT and Akita cells. Transfection of Akita cells with iPLA2β small interfering RNA, however, suppresses NSMase message, ΔΨ loss, and apoptosis. The iPLA2β gene contains a sterol-regulatory element, and transfection with a dominant negative SREBP-1 reduces basal mSREBP-1 and iPLA2β in the Akita cells and suppresses increases in mSREBP-1 and iPLA2β due to thapsigargin. These findings suggest that ER stress leads to generation of mSREBP-1, which can bind to the sterol-regulatory element in the iPLA2β gene to promote its transcription. Consistent with this, SREBP-1, iPLA2β, and NSMase messages in Akita mouse islets are higher than in WT islets.
Related Links	http://dx.doi.org/10.1074/jbc.m109.084293
Ending Page	6705
Page Count	13
Starting Page	6693
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	9
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-02-26
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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