Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2
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....
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/14/7598 |
| _version_ | 1797526908917776384 |
|---|---|
| author | Siddabasave Gowda B. Gowda Takayuki Tsukui Hirotoshi Fuda Yusuke Minami Divyavani Gowda Hitoshi Chiba Shu-Ping Hui |
| author_facet | Siddabasave Gowda B. Gowda Takayuki Tsukui Hirotoshi Fuda Yusuke Minami Divyavani Gowda Hitoshi Chiba Shu-Ping Hui |
| author_sort | Siddabasave Gowda B. Gowda |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:36:03Z |
| format | Article |
| id | doaj.art-267e87c421e84f9283ae8ce44311acd4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:36:03Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-267e87c421e84f9283ae8ce44311acd42023-11-22T04:01:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012214759810.3390/ijms22147598Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2Siddabasave Gowda B. Gowda0Takayuki Tsukui1Hirotoshi Fuda2Yusuke Minami3Divyavani Gowda4Hitoshi Chiba5Shu-Ping Hui6Faculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo 060-0812, JapanDepartment of Nutrition, Sapporo University of Health Sciences, Nakanuma Nishi-4-3-1-15, Higashi-ku, Sapporo 007-0894, JapanFaculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo 060-0812, JapanFaculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo 060-0812, JapanFaculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo 060-0812, JapanDepartment of Nutrition, Sapporo University of Health Sciences, Nakanuma Nishi-4-3-1-15, Higashi-ku, Sapporo 007-0894, JapanFaculty of Health Sciences, Hokkaido University, Kita 12, Nishi 5, Kita-ku, Sapporo 060-0812, JapanFatty 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.https://www.mdpi.com/1422-0067/22/14/7598FAHFAsDHANRF2lipid dropletHRMSLC/MS |
| spellingShingle | Siddabasave Gowda B. Gowda Takayuki Tsukui Hirotoshi Fuda Yusuke Minami Divyavani Gowda Hitoshi Chiba Shu-Ping Hui Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 International Journal of Molecular Sciences FAHFAs DHA NRF2 lipid droplet HRMS LC/MS |
| title | Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 |
| title_full | Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 |
| title_fullStr | Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 |
| title_full_unstemmed | Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 |
| title_short | Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 |
| title_sort | docosahexaenoic acid esters of hydroxy fatty acid is a novel activator of nrf2 |
| topic | FAHFAs DHA NRF2 lipid droplet HRMS LC/MS |
| url | https://www.mdpi.com/1422-0067/22/14/7598 |
| work_keys_str_mv | AT siddabasavegowdabgowda docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 AT takayukitsukui docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 AT hirotoshifuda docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 AT yusukeminami docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 AT divyavanigowda docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 AT hitoshichiba docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 AT shupinghui docosahexaenoicacidestersofhydroxyfattyacidisanovelactivatorofnrf2 |