Spontaneous development of endoplasmic reticulum stress that can lead to diabetes mellitus is associated with higher calcium-independent phospholipase A2 expression: a role for regulation by SREBP-1.

Abstract

Our recent studies indicate that endoplasmic reticulum (ER) stress causes INS-1 cell apoptosis by a Ca(2+)-independent phospholipase A(2) (iPLA(2)beta)-mediated mechanism that promotes ceramide generation via sphingomyelin hydrolysis and subsequent activation of the intrinsic pathway. To elucidate the association between iPLA(2)beta and ER stress, we compared beta-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 beta-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 iPLA(2)beta, mature SREBP-1 (mSREBP-1), phosphorylated Akt, and neutral sphingomyelinase (NSMase) are higher, relative abundances of sphingomyelins are lower, and mitochondrial membrane potential (DeltaPsi) is compromised in Akita cells, in comparison with WT cells. Exposure to thapsigargin accelerates DeltaPsi loss and apoptosis of Akita cells and is associated with increases in iPLA(2)beta, mSREBP-1, and NSMase in both WT and Akita cells. Transfection of Akita cells with iPLA(2)beta small interfering RNA, however, suppresses NSMase message, DeltaPsi loss, and apoptosis. The iPLA(2)beta gene contains a sterol-regulatory element, and transfection with a dominant negative SREBP-1 reduces basal mSREBP-1 and iPLA(2)beta in the Akita cells and suppresses increases in mSREBP-1 and iPLA(2)beta 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 iPLA(2)beta gene to promote its transcription. Consistent with this, SREBP-1, iPLA(2)beta, and NSMase messages in Akita mouse islets are higher than in WT islets.

• Authors: Xiaoyong Lei, Sheng Zhang, Suzanne E Barbour, Alan Bohrer, Eric L Ford, Akio Koizumi, Feroz R Papa, Sasanka Ramanadham
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 9 Pg. 6693-705 (Feb 26 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20032468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Phospholipases A2, Calcium-Independent

Topics

• Animals
• Apoptosis
• Binding Sites
• Diabetes Mellitus (etiology)
• Endoplasmic Reticulum (pathology)
• Humans
• Insulin-Secreting Cells
• Mice
• Mice, Transgenic
• Phospholipases A2, Calcium-Independent (genetics)
• Protein Binding
• Sterol Regulatory Element Binding Protein 1 (physiology)
• Stress, Physiological
• Transcription, Genetic