Choline And Apoptosis

Choline deficiency also resulted in an increase in apoptosis in a specific region of the hippocampus, namely the dentate gyrus. We observed an inverse correlation between apoptosis rates in the brains of rat fetuses and dietary intake of choline by their mothers (65). Others have reported apoptosis in the hippocampus and cortex of rats during the perinatal period (66,67); we were the first to report an effect of maternal nutrition. Apoptosis is usually inducible when cells are dividing and then undergo checkpoint arrest (68); cells in the resting phase are not susceptible (69). Why do cho-line-deficient cells die by apoptosis? Inhibition of transmethylation reactions by pharmacologic inhibitors (70,71) or by folate deficiency (72,73) can induce apoptotic cell death. However, because methyl supplementation with betaine, methionine, folate, or vitamin B12 did not prevent apoptotic death induced by choline deficiency in hepatocytes, it must be that depletion of intracellular choline moieties rather than depletion of methyl groups was the critical parameter involved in choline deficiency's induction of apoptosis (4). Synthesis of phosphatidylcholine is needed for progression of the cell cycle (53,59,74). Cells cultivated in choline-deficient medium are arrested in the G1 phase (53) and many studies have suggested that events during G1 can trigger apoptosis (75). Inhibition of phosphatidylcholine synthesis by pharmacological inhibitors induces apoptosis (76-81). This apoptotic cell death could be partially prevented by phosphatidylcholine or lysophos-phatidylcholine supplementation. All of these data suggest that phosphati-dylcholine is the critical molecule that is involved in protection from apoptosis. This hypothesis was supported by an observation that cells that were incapable of phosphatidylcholine synthesis by the CDP-choline pathway died by apoptosis (82) and by reports that a genetic defect in phosphati-dylcholine biosynthesis triggers apoptosis (83). We did not observe diminished phosphatidylcholine concentrations within fetal hippocampi from choline-deficient dams compared to choline-sufficient or supplemented groups (65). We did observe a significant increase in hippocampal phosphocholine concentrations in the supplemented group (65). Phospho-choline may be the important active derivative of choline in our brain model; in NIH 3T3 cells, generation of phosphocholine from phosphatidylcholine by phospholipase D and choline kinase is required for the induction of DNA synthesis (84).

Phosphatidylcholine is a precursor of another important phospholipid, sphingomyelin, and, in turn, sphingomyelin is a precursor for formation of ceramide. Ceramide is an important mediator of apoptosis (85) and we believe that it is an important intermediate in choline-deficiency-induced apoptosis. Ceramide concentrations increased prior to the increase in apoptosis in primary neuronal cells and in PC12 cells (refs. 6 and 85a). In PC12 cells, we previously demonstrated that exogenous ceramide induced apoptosis and that inhibition of choline-deficiency-induced apoptosis was associated with correction of intracellular ceramide levels (6). In several described paradigms of apoptosis, ceramide generated from sphingomyelin hydrolysis mediates apoptosis induced by stimuli such as tumor necrosis factor a, ultraviolet radiation, and activation of the CD95 receptor (86,87). Also, an increase in de novo ceramide synthesis may induce apoptosis

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