Astrocytes Release Polyunsaturated Fatty Acids by Lipopolysaccharide Stimuli

Abstract

We previously reported that levels of long-chain fatty acids (FAs) including docosahexaenoic acids (DHA) increase in the hypothalamus of inflammatory pain model mice. However, the precise mechanisms underlying the increment of free fatty acids (FFAs) in the brain during inflammation remains unknown. In this study, we characterized FFAs released by inflammatory stimulation in rat primary cultured astrocytes, and tested the involvement of phospholipase A 2 (PLA 2 ) on these mechanisms. Lipopolysaccharide (LPS) stimulation significantly increased the levels of several FAs in the astrocytes. Under these conditions, mRNA expression of cytosolic PLA 2 (cPLA 2 ) and calcium-independent PLA 2 (iPLA 2 ) in LPS-treated group increased compared with the control group. Furthermore, in the culture media, the levels of DHA and arachidonic acid (ARA) significantly increased by LPS stimuli compared with those of a vehicle-treated control group whereas the levels of saturated FAs (SFAs), namely palmitic acid (PAM) and stearic acid (STA), did not change. In summary, our findings suggest that astrocytes specifically release DHA and ARA by inflammatory conditions. Therefore astrocytes might function as a regulatory factor of DHA and ARA in the brain.Key words astrocyte; free fatty acid (FFA); inflammation; docosahexaenoic acid (DHA); phospholipase A 2 (PLA 2 ) Lipid is one of the necessary nutrients to keep homeostasis. Fatty acids (FAs) are the smallest unit that makes up Lipids. FAs are currently generating considerable attention as a major source of energy in the brain. In particular, a continuous supply of FAs is required for cellular metabolism, differentiation, and development of neuron.1-4) FAs served not only as cellular nutrients and cell membrane components but also as lipidsoluble signal molecules, suggesting that FAs play vital roles in a wide variety of physiological function. 5,6) The central nervous system (CNS) is enriched in lipids [7][8][9][10] and, in particular, brain consist of 20% polyunsaturated FAs (PUFAs) such as docosahexaenoic acid (DHA) and arachidonic acid (ARA). Furthermore, these PUFAs mainly relate the physiological function of the brain.Astrocytes, one of the glial cells, assume a crucial role to maintain brain and neuronal function via releasing glutamate or neurotrophic factors. In CNS, astrocytes but not neurons are the main source of DHA and ARA. DHA and ARA are released from astroglial membranes under basal and stimulated conditions such as neurotransmitters, bladykinin, glutamate, ATP and thrombin and are supplied to the neurons. [11][12][13][14] In our previous study, we demonstrated that hypothalamic long chain fatty acid (FA) levels increase in the early phase of complete Freund's adjuvant (CFA)-induced inflammatory pain.15) The DHA level, in particular, is significantly increased compared with the control group. These increases correlated with an increase in glial fibrillary acidic protein (GFAP) expression in the hypothalamus of CFA-treated mice and were inhibited by the suppression of as...

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