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....
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| Veröffentlicht in: | International journal of molecular sciences 2021-07, Vol.22 (14), p.7598 |
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| creator | B. Gowda, Siddabasave Gowda Tsukui, Takayuki Fuda, Hirotoshi Minami, Yusuke Gowda, Divyavani Chiba, Hitoshi Hui, Shu-Ping |
| 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. |
| doi_str_mv | 10.3390/ijms22147598 |
| format | Article |
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Gowda, Siddabasave Gowda ; Tsukui, Takayuki ; Fuda, Hirotoshi ; Minami, Yusuke ; Gowda, Divyavani ; Chiba, Hitoshi ; Hui, Shu-Ping</creator><creatorcontrib>B. Gowda, Siddabasave Gowda ; Tsukui, Takayuki ; Fuda, Hirotoshi ; Minami, Yusuke ; Gowda, Divyavani ; Chiba, Hitoshi ; Hui, Shu-Ping</creatorcontrib><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.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22147598</identifier><identifier>PMID: 34299218</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Androgens ; Antioxidants ; Biosynthesis ; Cytotoxicity ; Docosahexaenoic acid ; Esters ; Fatty acids ; Fluorescence ; Hepatoma ; Imaging techniques ; Lipid metabolism ; Lipids ; Liquid chromatography ; Liver cancer ; Mass spectrometry ; Mass spectroscopy ; Oleic acid ; Oxidation ; Oxidative stress ; Proteins ; Stearic acid ; Triglycerides</subject><ispartof>International journal of molecular sciences, 2021-07, Vol.22 (14), p.7598</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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Gowda, Siddabasave Gowda</creatorcontrib><creatorcontrib>Tsukui, Takayuki</creatorcontrib><creatorcontrib>Fuda, Hirotoshi</creatorcontrib><creatorcontrib>Minami, Yusuke</creatorcontrib><creatorcontrib>Gowda, Divyavani</creatorcontrib><creatorcontrib>Chiba, Hitoshi</creatorcontrib><creatorcontrib>Hui, Shu-Ping</creatorcontrib><title>Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2</title><title>International journal of molecular sciences</title><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.</description><subject>Androgens</subject><subject>Antioxidants</subject><subject>Biosynthesis</subject><subject>Cytotoxicity</subject><subject>Docosahexaenoic acid</subject><subject>Esters</subject><subject>Fatty acids</subject><subject>Fluorescence</subject><subject>Hepatoma</subject><subject>Imaging techniques</subject><subject>Lipid metabolism</subject><subject>Lipids</subject><subject>Liquid chromatography</subject><subject>Liver cancer</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Oleic acid</subject><subject>Oxidation</subject><subject>Oxidative stress</subject><subject>Proteins</subject><subject>Stearic acid</subject><subject>Triglycerides</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkU9Lw0AQxRdRbK3e_AABLx6M7p9sNnsRSm1toVQQPS-b7MSmpNm6m5Tm25vSItXTzPB-vJnhIXRL8CNjEj8Vq7WnlESCy-QM9UlEaYhxLM5P-h668n6FMWWUy0vUYxGVkpKkjxYvNrNeL2GnobJFFgyzwgRjX4Pzgc2DaWuc3bXBRNd1exBnPtDBwm6h7Oa62Orauj26eJ_Qa3SR69LDzbEO0Odk_DGahvO319loOA-zSMo6zGMwBscJ1ZkQQpLcYCIlhjwlMjJMQtRdzmMsGBgBOSZcMg6J1likJhWGDdDzwXfTpGswGVS106XauGKtXausLtRfpSqW6stuVcK6tZh0BvdHA2e_G_C1Whc-g7LUFdjGK8o5J4RSEXfo3T90ZRtXde_tqYjHgiW8ox4OVOas9w7y32MIVvug1GlQ7AdC6YPV</recordid><startdate>20210715</startdate><enddate>20210715</enddate><creator>B. 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Gowda, Siddabasave Gowda ; Tsukui, Takayuki ; Fuda, Hirotoshi ; Minami, Yusuke ; Gowda, Divyavani ; Chiba, Hitoshi ; Hui, Shu-Ping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-f6edd0682ac77791fd01990efb194d39e442256073ed7ef015935e8aa07bdb7d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Androgens</topic><topic>Antioxidants</topic><topic>Biosynthesis</topic><topic>Cytotoxicity</topic><topic>Docosahexaenoic acid</topic><topic>Esters</topic><topic>Fatty acids</topic><topic>Fluorescence</topic><topic>Hepatoma</topic><topic>Imaging techniques</topic><topic>Lipid metabolism</topic><topic>Lipids</topic><topic>Liquid chromatography</topic><topic>Liver cancer</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Oleic acid</topic><topic>Oxidation</topic><topic>Oxidative stress</topic><topic>Proteins</topic><topic>Stearic acid</topic><topic>Triglycerides</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>B. Gowda, Siddabasave Gowda</creatorcontrib><creatorcontrib>Tsukui, Takayuki</creatorcontrib><creatorcontrib>Fuda, Hirotoshi</creatorcontrib><creatorcontrib>Minami, Yusuke</creatorcontrib><creatorcontrib>Gowda, Divyavani</creatorcontrib><creatorcontrib>Chiba, Hitoshi</creatorcontrib><creatorcontrib>Hui, Shu-Ping</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>B. Gowda, Siddabasave Gowda</au><au>Tsukui, Takayuki</au><au>Fuda, Hirotoshi</au><au>Minami, Yusuke</au><au>Gowda, Divyavani</au><au>Chiba, Hitoshi</au><au>Hui, Shu-Ping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2</atitle><jtitle>International journal of molecular sciences</jtitle><date>2021-07-15</date><risdate>2021</risdate><volume>22</volume><issue>14</issue><spage>7598</spage><pages>7598-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34299218</pmid><doi>10.3390/ijms22147598</doi><orcidid>https://orcid.org/0000-0002-7972-9982</orcidid><orcidid>https://orcid.org/0000-0003-4640-7730</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Androgens Antioxidants Biosynthesis Cytotoxicity Docosahexaenoic acid Esters Fatty acids Fluorescence Hepatoma Imaging techniques Lipid metabolism Lipids Liquid chromatography Liver cancer Mass spectrometry Mass spectroscopy Oleic acid Oxidation Oxidative stress Proteins Stearic acid Triglycerides |
| title | Docosahexaenoic Acid Esters of Hydroxy Fatty Acid Is a Novel Activator of NRF2 |
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