Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid
Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2018-06, Vol.67 (6), p.1190-1199 |
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| creator | Kuda, Ondrej Brezinova, Marie Silhavy, Jan Landa, Vladimir Zidek, Vaclav Dodia, Chandra Kreuchwig, Franziska Vrbacky, Marek Balas, Laurence Durand, Thierry Hübner, Norbert Fisher, Aron B Kopecky, Jan Pravenec, Michal |
| description | Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 (
)-mediated antioxidant defense system (
), lipid-handling proteins (
), and the family of flavin containing monooxygenases (
) as the positional candidate genes. Transgenic expression of
and deletion of
genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues. |
| doi_str_mv | 10.2337/db17-1087 |
| format | Article |
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)-mediated antioxidant defense system (
), lipid-handling proteins (
), and the family of flavin containing monooxygenases (
) as the positional candidate genes. Transgenic expression of
and deletion of
genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db17-1087</identifier><identifier>PMID: 29549163</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Adipose tissue ; Adipose Tissue, White - enzymology ; Adipose Tissue, White - metabolism ; Animal models ; Animals ; Antagonist drugs ; Anti-inflammatory agents ; Antidiabetics ; Antioxidants ; Biomarkers - metabolism ; CD36 antigen ; Diabetes ; Diabetes mellitus ; Esters ; Esters - chemistry ; Esters - metabolism ; Fatty acids ; Female ; Flavin ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic ; Genetics/Genomes/Proteomics/Metabolomics ; Glucose ; Glutathione ; Hypoglycemia ; Inbreeding ; Inflammation ; Insulin ; Life Sciences ; Linkage analysis ; Lipogenesis ; Male ; Metabolomics - methods ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; Oxidative Stress ; Palmitic acid ; Palmitic Acid - chemistry ; Palmitic Acid - metabolism ; Peroxiredoxin ; Peroxiredoxin VI - genetics ; Peroxiredoxin VI - metabolism ; Pharmacology ; Quantitative trait loci ; Random Allocation ; Rats ; Rats, Inbred BN ; Rats, Inbred SHR ; Rats, Transgenic ; Stearic Acids - chemistry ; Stearic Acids - metabolism</subject><ispartof>Diabetes (New York, N.Y.), 2018-06, Vol.67 (6), p.1190-1199</ispartof><rights>2018 by the American Diabetes Association.</rights><rights>Copyright American Diabetes Association Jun 1, 2018</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2018 by the American Diabetes Association. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c437t-b58746e4fe6c506273ab507d5386425ef8c335725d7f508c248f97e128d649813</citedby><cites>FETCH-LOGICAL-c437t-b58746e4fe6c506273ab507d5386425ef8c335725d7f508c248f97e128d649813</cites><orcidid>0000-0001-7034-4536 ; 0000-0002-6687-3811 ; 0000-0001-6086-7296</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463562/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463562/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29549163$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03550402$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuda, Ondrej</creatorcontrib><creatorcontrib>Brezinova, Marie</creatorcontrib><creatorcontrib>Silhavy, Jan</creatorcontrib><creatorcontrib>Landa, Vladimir</creatorcontrib><creatorcontrib>Zidek, Vaclav</creatorcontrib><creatorcontrib>Dodia, Chandra</creatorcontrib><creatorcontrib>Kreuchwig, Franziska</creatorcontrib><creatorcontrib>Vrbacky, Marek</creatorcontrib><creatorcontrib>Balas, Laurence</creatorcontrib><creatorcontrib>Durand, Thierry</creatorcontrib><creatorcontrib>Hübner, Norbert</creatorcontrib><creatorcontrib>Fisher, Aron B</creatorcontrib><creatorcontrib>Kopecky, Jan</creatorcontrib><creatorcontrib>Pravenec, Michal</creatorcontrib><title>Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 (
)-mediated antioxidant defense system (
), lipid-handling proteins (
), and the family of flavin containing monooxygenases (
) as the positional candidate genes. Transgenic expression of
and deletion of
genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.</description><subject>Adipose tissue</subject><subject>Adipose Tissue, White - enzymology</subject><subject>Adipose Tissue, White - metabolism</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antagonist drugs</subject><subject>Anti-inflammatory agents</subject><subject>Antidiabetics</subject><subject>Antioxidants</subject><subject>Biomarkers - metabolism</subject><subject>CD36 antigen</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Esters</subject><subject>Esters - chemistry</subject><subject>Esters - metabolism</subject><subject>Fatty acids</subject><subject>Female</subject><subject>Flavin</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Genetics/Genomes/Proteomics/Metabolomics</subject><subject>Glucose</subject><subject>Glutathione</subject><subject>Hypoglycemia</subject><subject>Inbreeding</subject><subject>Inflammation</subject><subject>Insulin</subject><subject>Life Sciences</subject><subject>Linkage analysis</subject><subject>Lipogenesis</subject><subject>Male</subject><subject>Metabolomics - methods</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxidative Stress</subject><subject>Palmitic acid</subject><subject>Palmitic Acid - chemistry</subject><subject>Palmitic Acid - metabolism</subject><subject>Peroxiredoxin</subject><subject>Peroxiredoxin VI - genetics</subject><subject>Peroxiredoxin VI - metabolism</subject><subject>Pharmacology</subject><subject>Quantitative trait loci</subject><subject>Random Allocation</subject><subject>Rats</subject><subject>Rats, Inbred BN</subject><subject>Rats, Inbred SHR</subject><subject>Rats, Transgenic</subject><subject>Stearic Acids - chemistry</subject><subject>Stearic Acids - metabolism</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUk1vEzEUtBCIpoUDfwBZ4kIPC_727gVpKYUgBegBJG6Ws35LXDZ2sZ2K3PjpeNVQoLJkS_Pmzdh-g9ATSl4wzvVLt6a6oaTV99CCdrxrONNf76MFIZQ1VHf6CB3nfEkIUXU9REesk6Kjii_Qr49pZM0HcN4WcLgPxcef3tlQ8BsYIWTANjh8AanCCVzdA1a4T4BXPnyvLSXi1z7mfSgbyD7jOOILO2198QPuB-_weS6QZrhrlntXdfYVsOlQfoQejHbK8PhwnqAvb88_ny2b1ad378_6VTMIrkuzlq0WCsQIapBEMc3tWhLtJG-VYBLGduBcaiadHiVpBybasdNAWeuU6FrKT9CrG92r3XoLboBQkp3MVfJbm_YmWm_-rwS_Md_itVFCcalYFTi9EdjcaVv2KzNjhEtJBGHXs9nzg1mKP3aQi9n6PMA02QBxlw0jVHRSSTpTn92hXsZdCvUrDKsjbZUmUvw1H1LMOcF4ewNKzJwBM2fAzBmo3Kf_vvSW-Wfo_DczgarO</recordid><startdate>20180601</startdate><enddate>20180601</enddate><creator>Kuda, Ondrej</creator><creator>Brezinova, Marie</creator><creator>Silhavy, Jan</creator><creator>Landa, Vladimir</creator><creator>Zidek, Vaclav</creator><creator>Dodia, Chandra</creator><creator>Kreuchwig, Franziska</creator><creator>Vrbacky, Marek</creator><creator>Balas, Laurence</creator><creator>Durand, Thierry</creator><creator>Hübner, Norbert</creator><creator>Fisher, Aron B</creator><creator>Kopecky, Jan</creator><creator>Pravenec, Michal</creator><general>American Diabetes Association</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7034-4536</orcidid><orcidid>https://orcid.org/0000-0002-6687-3811</orcidid><orcidid>https://orcid.org/0000-0001-6086-7296</orcidid></search><sort><creationdate>20180601</creationdate><title>Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid</title><author>Kuda, Ondrej ; Brezinova, Marie ; Silhavy, Jan ; Landa, Vladimir ; Zidek, Vaclav ; Dodia, Chandra ; Kreuchwig, Franziska ; Vrbacky, Marek ; Balas, Laurence ; Durand, Thierry ; Hübner, Norbert ; Fisher, Aron B ; Kopecky, Jan ; Pravenec, Michal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-b58746e4fe6c506273ab507d5386425ef8c335725d7f508c248f97e128d649813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adipose tissue</topic><topic>Adipose Tissue, White - enzymology</topic><topic>Adipose Tissue, White - metabolism</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antagonist drugs</topic><topic>Anti-inflammatory agents</topic><topic>Antidiabetics</topic><topic>Antioxidants</topic><topic>Biomarkers - metabolism</topic><topic>CD36 antigen</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Esters</topic><topic>Esters - chemistry</topic><topic>Esters - metabolism</topic><topic>Fatty acids</topic><topic>Female</topic><topic>Flavin</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Genetics/Genomes/Proteomics/Metabolomics</topic><topic>Glucose</topic><topic>Glutathione</topic><topic>Hypoglycemia</topic><topic>Inbreeding</topic><topic>Inflammation</topic><topic>Insulin</topic><topic>Life Sciences</topic><topic>Linkage analysis</topic><topic>Lipogenesis</topic><topic>Male</topic><topic>Metabolomics - methods</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Oxidative Stress</topic><topic>Palmitic acid</topic><topic>Palmitic Acid - chemistry</topic><topic>Palmitic Acid - metabolism</topic><topic>Peroxiredoxin</topic><topic>Peroxiredoxin VI - genetics</topic><topic>Peroxiredoxin VI - metabolism</topic><topic>Pharmacology</topic><topic>Quantitative trait loci</topic><topic>Random Allocation</topic><topic>Rats</topic><topic>Rats, Inbred BN</topic><topic>Rats, Inbred SHR</topic><topic>Rats, Transgenic</topic><topic>Stearic Acids - chemistry</topic><topic>Stearic Acids - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kuda, Ondrej</creatorcontrib><creatorcontrib>Brezinova, Marie</creatorcontrib><creatorcontrib>Silhavy, Jan</creatorcontrib><creatorcontrib>Landa, Vladimir</creatorcontrib><creatorcontrib>Zidek, Vaclav</creatorcontrib><creatorcontrib>Dodia, Chandra</creatorcontrib><creatorcontrib>Kreuchwig, Franziska</creatorcontrib><creatorcontrib>Vrbacky, Marek</creatorcontrib><creatorcontrib>Balas, Laurence</creatorcontrib><creatorcontrib>Durand, Thierry</creatorcontrib><creatorcontrib>Hübner, Norbert</creatorcontrib><creatorcontrib>Fisher, Aron B</creatorcontrib><creatorcontrib>Kopecky, Jan</creatorcontrib><creatorcontrib>Pravenec, Michal</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuda, Ondrej</au><au>Brezinova, Marie</au><au>Silhavy, Jan</au><au>Landa, Vladimir</au><au>Zidek, Vaclav</au><au>Dodia, Chandra</au><au>Kreuchwig, Franziska</au><au>Vrbacky, Marek</au><au>Balas, Laurence</au><au>Durand, Thierry</au><au>Hübner, Norbert</au><au>Fisher, Aron B</au><au>Kopecky, Jan</au><au>Pravenec, Michal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2018-06-01</date><risdate>2018</risdate><volume>67</volume><issue>6</issue><spage>1190</spage><epage>1199</epage><pages>1190-1199</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 (
)-mediated antioxidant defense system (
), lipid-handling proteins (
), and the family of flavin containing monooxygenases (
) as the positional candidate genes. Transgenic expression of
and deletion of
genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>29549163</pmid><doi>10.2337/db17-1087</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-7034-4536</orcidid><orcidid>https://orcid.org/0000-0002-6687-3811</orcidid><orcidid>https://orcid.org/0000-0001-6086-7296</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2018-06, Vol.67 (6), p.1190-1199 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6463562 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adipose tissue Adipose Tissue, White - enzymology Adipose Tissue, White - metabolism Animal models Animals Antagonist drugs Anti-inflammatory agents Antidiabetics Antioxidants Biomarkers - metabolism CD36 antigen Diabetes Diabetes mellitus Esters Esters - chemistry Esters - metabolism Fatty acids Female Flavin Gene Expression Profiling Gene Expression Regulation, Enzymologic Genetics/Genomes/Proteomics/Metabolomics Glucose Glutathione Hypoglycemia Inbreeding Inflammation Insulin Life Sciences Linkage analysis Lipogenesis Male Metabolomics - methods Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Oxidative Stress Palmitic acid Palmitic Acid - chemistry Palmitic Acid - metabolism Peroxiredoxin Peroxiredoxin VI - genetics Peroxiredoxin VI - metabolism Pharmacology Quantitative trait loci Random Allocation Rats Rats, Inbred BN Rats, Inbred SHR Rats, Transgenic Stearic Acids - chemistry Stearic Acids - metabolism |
| title | Nrf2-Mediated Antioxidant Defense and Peroxiredoxin 6 Are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid |
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