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CDP‐CHOLINE PARTLY RESTORES THE PHOSPHATIDYLCHOLINE LEVELS BY DIFFERENTIALLY AFFECTING SECRETORY PHOSPHOLIPASE A 2 IIA AND CTP‐PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE AFTER STROKE
Author(s) -
Adibhatla Rao M,
Hatcher James F,
Larsen Eric C,
Chen Xinzhi,
Sun Dandan,
Dempsey Robert J
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a87-a
Subject(s) - phosphocholine , phosphatidylcholine , choline , choline kinase , pld2 , phospholipase , phospholipase c , chemistry , phosphatidylethanol , medicine , phospholipid , phospholipase a2 , endocrinology , biology , biochemistry , signal transduction , enzyme , membrane
Phosphatidylcholine (PtdCho) is a major membrane phospholipid and its loss is sufficient in itself to induce cell death. PtdCho homeostasis is regulated by a balance between hydrolysis and synthesis. PtdCho is hydrolyzed by phospholipase A 2 (PLA 2 ), PtdCho‐phospholipase C (PtdCho‐PLC) and phospholipase D (PLD). PtdCho synthesis is rate‐limited by CTP:phosphocholine cytidylyltransferase (CCT) that makes CDP‐choline. The final step of PtdCho synthesis is catalyzed by CDP‐choline: 1,2‐diacylglycerol choline phosphotransferase (CPT). PtdCho synthesis in the brain is predominantly through the CDP‐choline pathway. Transient middle cerebral artery occlusion (tMCAO) significantly increased secretory PLA 2 (sPLA 2 ) IIA mRNA and protein levels, PtdCho‐PLC activity and PLD2 expression at 1 d reperfusion. CDP‐choline treatment significantly attenuated sPLA 2 mRNA and protein levels and PtdCho‐PLC activity, but did not affect PLD2 expression. tMCAO also resulted in loss of CCT activity and protein that were partially restored by CDP‐choline. No changes were observed in the cytosolic PLA 2 or calcium‐independent PLA 2 protein levels after tMCAO. The up‐regulation of phospholipases and loss of CCT collectively resulted in the loss of PtdCho and total phospholipids, which were partially restored by CDP‐choline. CDP‐choline treatment significantly attenuated the infarction volume by 55% ± 5 after stroke. TNF‐α and IL‐1α/β are up‐regulated in the brain after stroke. TNF‐α/IL‐1 activate phospholipases and down‐regulate CCT, thus increasing PtdCho hydrolysis and inhibiting PtdCho synthesis. Our studies integrate CDP‐choline effects with cytokine biology and lipid metabolism in stroke. Support: NIH UW VA.