The protective effects of stearidonic acid on adipogenesis and neurotoxicity

Abstract

Abstract

The ω-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in fish oil have been reported to have protective effects on metabolic syndrome-related diseases, such as obesity and alzheimer’s disease (AD). Stearidonic acid (SDA) is a plant-based ω-3 PUFA that serves as the metabolic precursor of EPA. SDA has been shown to have similar metabolic effects to DHA and EPA. This dissertation was aimed to investigate whether SDA has similar effects to DHA and EPA on obesity and AD. Obesity is characterized at the cellular level by an increase in the number and size of adipocytes differentiated from preadipocytes. The ω-3 PUFAs found in fish oil have been shown to have anti-obesity effects through inhibition of adipocyte differentiation. In the 3T3-L1 cell model, we demonstrated that SDA treatment led to significantly greater EPA enrichment compared to ALA-treated cells. In addition, SDA treatment, similar to EPA and DHA, inhibited fat storage in 3T3-L1 cells indicated by decreased accumulation of lipid droplets and reduced triglyceride (TG) content. Further, we demonstrated that this anti-adipogenic effect by SDA may rely on its down-regulation of mRNA levels of the adipogenic transcription factor, SREBP-1c, and the lipid accumulation genes, AP2, FAS, SCD-1, LPL, GLUT4, and PEPCK. In summary, SDA is able to suppress the adipocyte differentiation and lipid accumulation by affecting the expression of associated genes. Our findings warrant further study to develop SDA as a natural and effective agent in the prevention or treatment of obesity. AD involves an amyloid-beta (Aβ)-induced cascade of an increase in apoptosis, oxidative stress, and inflammation. DHA and EPA have been shown to protect against Aβ-induced neurotoxicity through modulation of this cascade. In the H19-7 hippocampal cell model, we demonstrated that SDA treatment led to significantly greater EPA enrichment compared to ALA-treated cells. Moreover, SDA significantly decreased neuronal death by inhibition of caspase activation and regulation of apoptotic Bcl-2 family gene expression. Total anti-oxidant capacity was significantly increased in SDA-treated cells through increased catalase activity and up-regulation of anti-oxidative gene expression, such as GPx, GSR, and SOD. SDA significantly decreased Aβ and LPS-induced expression of pro-inflammatory mediators, IL-6, TNFα, COX-2, MCP-1 and TLR4. SDA exerted neuroprotective effects through attenuation of Aβ-induced JNK and p38 phosphorylation, and enhancement of ERK phosphorylation depressed by Aβ. Importantly, the efficacy of neuroprotective effects by SDA is more significant than that of ALA, and comparable to that of EPA and DHA. In summary, SDA protects against Aβ-induced neurotoxicity in hippocampal neurons. Our findings warrant further study to develop SDA as a natural and effective agent in the prevention or treatment of AD. It is known that ω-3 PUFAs exert their biologic activities via formation of eicosanoids by competing with ω-6 PUFAs. Generally, ω-3 derived eicosanoids are less potent than analogous ω-6 derived eicosanoids. However, to date, only a few studies have investigated the overall effects on eicosanoid production by ω-3 fatty acids and no study has been conducted on SDA treatment. The present study conducted a lipidomics study to characterize the changes in eicosanoid profile in H19-7 rat hippocampal cells upon treatment of different ω-3 fatty acids. Our results showed that 1) ω-3 fatty acids affect the production of eicosanoids by LOX, COX, CYP, and non-enzymatic autoxidation pathways; 2) ω-3 fatty acids are natural anti-inflammatory compounds that can convert to a lot of anti-inflammatory eicosanoids under normal conditions; 3) ω-3 fatty acids, especially EPA can also increase the production of many pro-inflammatory metabolites; 4) treatment of DHA can increase the ROS production. In general, the effects on eicosanoid production are consistent among all four ω-3 fatty acids and the efficacy of anti-inflammatory potent is DHA&EPA > SDA >> ALA. Particularly, the changing pattern of eicosanoids affected by SDA treatment is most close to the pattern by EPA, which confirmed the proposal that SDA is the surrogate for EPA. Importantly, compared to EPA, SDA is much less potent in increasing the production of anti-inflammatory metabolites, but also much less potent in increasing the production of pro-inflammatory metabolites, suggesting that SDA may have advantages over EPA. Moreover, data suggest that SDA has its unique roles in biosynthesis of eicosanoids, such as decreased PGD1 level, suggesting that SDA may have its own specific biological functions different from DHA and EPA. Finally, this lipidomics study of ω-3 fatty acids is valuable and provides lots of inspirations for future studies, especially in the area of chronic inflammatory diseases, the area of cardiovascular system where ω-3 fatty acids act as vasodilator, and the area of host immune defense.