n−3 Fatty acid deficiency decreases phosphatidylserine accumulation selectively in neuronal tissues

Abstract

We have previously shown that the docosahexaenoate (22:6n-3) status in membrane phospholipids influences the biosynthesis and accumulation of phosphatidylserine (PS) in brain microsomes and C6 glioma cells. In the present study, we investigated whether the observed effect of membrane docosahexaenoic acid status on PS accumulation is universal or occurs specifically in neuronal tissues. We observed that rat brain cortex, brain mitochondria, and olfactory bulb, where 22:6n-3 is highly concentrated, contain significantly higher levels of PS in comparison to liver and adrenal, where 22:6n-3 is a rather minor component. Phospholipid molecular species analysis revealed that in brain cortex, mitochondria, and olfactory bulb 18:0,22:6n-3 was the most abundant species representing 45-65% of total PS. In nonneuronal tissues such as liver and adrenal, 18:0,20:4n-6 was the major PS species. Dietary depletion of n-3 fatty acids during prenatal and postnatal developmental periods decreased the brain 22:6n-3 content by more than 80%, with a concomitant increase in 22:5n-6 in all tissues. Under these conditions, an approximately 30-35% reduction in total PS in rat brain cortex, brain mitochondria, and olfactory bulb was observed, while PS levels in liver and adrenal were unchanged. The observed reduction of PS content in neuronal membranes appears to be due to a dramatic reduction of 18:0,22:6n-3-PS without complete replacement by 18:0,22:5n-6-PS. These results establish that variations in membrane 22:6n-3 fatty acid composition have a profound influence on PS accumulation in neuronal tissues where 22:6n-3 is abundant. These data have implications in neuronal signaling events where PS is believed to play an important role.

Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival

“…Similarly, DHA supplementation in cultured glia or neuronal cells has been shown to increase PS content (20,21). In contrast, depletion of DHA under n-3 fatty acid deficiency led to a reduced PS level in neuronal tissues, including rat brain cortex, hippocampus, pineal, and olfactory system (22)(23)(24), despite the compensatory replacement of DHA with DPA. Consistently, DHA containing phospholipids were found to be the preferred substrate to DPA species for PS biosynthesis (25).…”

Mechanisms of action of docosahexaenoic acid in the nervous system

“…In neuronal membranes, DHA is highly enriched in aminophospholipids, especially PS (1,2,4,5-10,114). We and others have previously demonstrated that the enrichment of DHA in cell membranes increases PS synthesis and, conversely, that depletion of this fatty acid by an n-3-deficient diet or by chronic ethanol exposure decreases the accumulation of PS (115)(116)(117)(118). Considering the fact that PS is the major negatively charged phospholipid class in many mammalian cell membranes and many of the signaling proteins such as protein kinases are influenced by PS (119-121), this alteration of PS content may have significant implications for cellular function.…”

The Biochemistry of n-3 Polyunsaturated Fatty Acids

“…Astrocytes, but not neurons, make 22:6n-3, thus providing a potential source of 22:6n-3 to activate RXR␣ (15). Second, n-3 PUFA deficiency is correlated with a decline in PS and increased neuronal apoptosis (11,30,31). Neuronal apoptosis is linked to Raf-1 and plasma membrane PS content.…”