Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo 060-0812, Japan.
Department of Nutrition, Sapporo University of Health Sciences, Nakanuma Nishi-4-3-1-15, Higashi-ku, Sapporo 007-0894, Japan.
Int J Mol Sci. 2021 Jul 15;22(14):7598. doi: 10.3390/ijms22147598.
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with interesting physiological functions in mammals. Despite their structural diversity and links with nuclear factor erythroid 2-related factor 2 (NRF2) biosynthesis, FAHFAs are less explored as NRF2 activators. Herein, we examined for the first time the synthetic docosahexaenoic acid esters of 12-hydroxy stearic acid (12-DHAHSA) or oleic acid (12-DHAHOA) against NRF2 activation in cultured human hepatoma-derived cells (C3A). The effect of DHA-derived FAHFAs on lipid metabolism was explored by the nontargeted lipidomic analysis using liquid chromatography-mass spectrometry. Furthermore, their action on lipid droplet (LD) oxidation was investigated by the fluorescence imaging technique. The DHA-derived FAHFAs showed less cytotoxicity compared to their native fatty acids and activated the NRF2 in a dose-dependent pattern. Treatment of 12-DHAHOA with C3A cells upregulated the cellular triacylglycerol levels by 17-fold compared to the untreated group. Fluorescence imaging analysis also revealed the suppression of the degree of LDs oxidation upon treatment with 12-DHAHSA. Overall, these results suggest that DHA-derived FAHFAs as novel and potent activators of NRF2 with plausible antioxidant function.
羟基脂肪酸的脂肪酸酯（FAHFAs）是一类具有有趣生理功能的新型内源性脂质，在哺乳动物中。尽管它们的结构多样性和与核因子红细胞 2 相关因子 2（NRF2）生物合成有关，但作为 NRF2 激活剂的 FAHFAs 研究较少。本文首次研究了合成的二十二碳六烯酸酯 12-羟基硬脂酸（12-DHAHSA）或油酸（12-DHAHOA）对培养的人肝癌衍生细胞（C3A）中 NRF2 激活的作用。通过使用液相色谱-质谱的非靶向脂质组学分析，探讨了 DHA 衍生的 FAHFAs 对脂质代谢的影响。此外，还通过荧光成像技术研究了它们对脂滴（LD）氧化的作用。与天然脂肪酸相比，DHA 衍生的 FAHFAs 表现出较低的细胞毒性，并以剂量依赖性方式激活 NRF2。与未处理组相比，12-DHAHOA 处理 C3A 细胞可使细胞三酰甘油水平增加 17 倍。荧光成像分析还显示，用 12-DHAHSA 处理可抑制 LDs 氧化的程度。总的来说，这些结果表明，DHA 衍生的 FAHFAs 作为新型、有效的 NRF2 激活剂，具有潜在的抗氧化功能。
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