{"id":30132,"date":"2024-08-23T20:15:41","date_gmt":"2024-08-23T18:15:41","guid":{"rendered":"https:\/\/fgu.antstudio.dev\/?post_type=vyzkumny-projekt&#038;p=30132"},"modified":"2024-10-29T15:18:37","modified_gmt":"2024-10-29T14:18:37","slug":"anti-inflammatory-effects-of-novel-lipokines-of-fatty-acid-esters-of-hydroxy-fatty-acids-fahfa-family-in-obesity","status":"publish","type":"vyzkumny-projekt","link":"https:\/\/fgu.cas.cz\/en\/research-project\/anti-inflammatory-effects-of-novel-lipokines-of-fatty-acid-esters-of-hydroxy-fatty-acids-fahfa-family-in-obesity\/","title":{"rendered":"Anti-inflammatory effects of novel lipokines of fatty acid esters of hydroxy fatty acids (FAHFA) family in obesity"},"content":{"rendered":"<div class=\"main-image\"><img fetchpriority=\"high\" decoding=\"async\" class=\"alignnone size-full wp-image-27431\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/ugct3l0690bpblqk4mov.jpg\" alt=\"-\" width=\"700\" height=\"250\" title=\"\" srcset=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/ugct3l0690bpblqk4mov.jpg 700w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/ugct3l0690bpblqk4mov-300x107.jpg 300w\" sizes=\"(max-width: 700px) 100vw, 700px\" \/><\/div>\n<div class=\"content full\">\n<div>\n<p>White adipose tissue (WAT) is a complex endocrine organ and its low-grade inflammation in obesity contributes to the development of metabolic disorders. In 2014, a class of WAT-born lipid mediators &#8211; fatty acid esters of hydroxy fatty acids (FAHFA) was discovered [1]. FAHFAs are endogenous lipids with anti-inflammatory and anti-diabetic properties, including the enhancement of glucose tolerance, and insulin and glucagon-like peptide 1 (GLP-1) secretion while reducing inflammatory responses [1-5]. They consist of a fatty acid (e.g. palmitic acid, PA) esterified to the hydroxyl group of a hydroxy fatty acid (e.g. hydroxystearic acid, HSA), abbreviated as PAHSA. The position of the branching carbon defines a regioisomer (e.g. 5-PAHSA). There are several regioisomer families derived from palmitic, palmitoleic, stearic, oleic, linoleic, and docosahexaenoic acid with tissue-specific distribution documented so far [1-4, 6, 7]. Adipose tissue represents a major site of FAHFAs synthesis [1, <a href=\"https:\/\/www.fgu.cas.cz\/en\/articles\/648-protizanetlive-ucinky-novych-lipokinu-z-rodiny-vetvenych-esteru-mastnych-kyselin-fahfa-pri-obezite#DHAHLA\">2<\/a>], but the biosynthetic enzymes involved are unknown [<a href=\"https:\/\/www.fgu.cas.cz\/en\/articles\/648-protizanetlive-ucinky-novych-lipokinu-z-rodiny-vetvenych-esteru-mastnych-kyselin-fahfa-pri-obezite#\">11<\/a>]. Serine hydrolase carboxyl ester lipase [8] and threonine hydrolases [9] were identified as FAHFA-metabolizing enzymes. In humans, FAHFAs were detected in the serum, breast milk, meconium, and adipose tissues [1, <a href=\"https:\/\/www.fgu.cas.cz\/en\/articles\/648-protizanetlive-ucinky-novych-lipokinu-z-rodiny-vetvenych-esteru-mastnych-kyselin-fahfa-pri-obezite#DHAHLA\">2<\/a>, <a href=\"https:\/\/www.fgu.cas.cz\/en\/articles\/648-protizanetlive-ucinky-novych-lipokinu-z-rodiny-vetvenych-esteru-mastnych-kyselin-fahfa-pri-obezite#milk\">10<\/a>].<\/p>\n<p>Example of PAHSA regioisomers:<br \/>\n<img decoding=\"async\" class=\"alignnone wp-image-30133\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsas.gif\" alt=\"-\" width=\"434\" height=\"145\" title=\"\"><\/p>\n<p><strong>Network representation of FAHFA families<\/strong> linked according to the hydroxy-backbone and colored according to the esterified fatty acid [<a href=\"https:\/\/www.fgu.cas.cz\/en\/articles\/648-protizanetlive-ucinky-novych-lipokinu-z-rodiny-vetvenych-esteru-mastnych-kyselin-fahfa-pri-obezite#QTL\">11<\/a>] (click for full image).<\/p>\n<p><img decoding=\"async\" class=\"size-large wp-image-27433 aligncenter\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/fahfa-network-1-1024x652.jpg\" alt=\"-\" width=\"800\" height=\"509\" title=\"\" srcset=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/fahfa-network-1-1024x652.jpg 1024w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/fahfa-network-1-300x191.jpg 300w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/fahfa-network-1-768x489.jpg 768w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/fahfa-network-1-1536x978.jpg 1536w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/fahfa-network-1-2048x1304.jpg 2048w\" sizes=\"(max-width: 800px) 100vw, 800px\" \/><\/p>\n<div>\n<p>Our hypothesis is that novel FAHFAs derived\u00a0 from omega-3 PUFA, with anti-inflammatory\u00a0 properties, could be found in mice and humans and that they can beneficially affect adipose tissue metabolism in obesity,\u00a0 especially low-grade\u00a0 inflammation. We are also interested in FAHFA metabolic pathways, which seem to be as complex as eicosanoid-related pathways. Using experiments in cell cultures, mice and humans we explore\u00a0 the structures, effects\u00a0 on WAT inflammation,\u00a0 WAT glucose tolerance and molecular\u00a0 mechanisms of signaling\u00a0 of these new lipokines. Our results present a significant advance in research of the mechanisms connecting inflammation, metabolism, and nutritional lipids.<\/p>\n<\/div>\n<h2>Metabolomics lab team members:<\/h2>\n<ul>\n<li><b>Ondrej Kuda (PI)<\/b><\/li>\n<li>Marie Brezinova (PhD student)<\/li>\n<li>Martina Rombaldova (PhD student)<\/li>\n<li>Marina Oseeva (PhD student)<\/li>\n<li>Daniela Salkova (technician)<\/li>\n<\/ul>\n<h2>Grants<\/h2>\n<p>Supported by:<\/p>\n<ul>\n<li>Czech Science Foundation project no. 17-10088Y (2017-2019, PI: Ondrej Kuda)<\/li>\n<li>MEYS project no. LTAUSA17173 (2017-2019, PI: Ondrej Kuda)<\/li>\n<li>MEYS project no. LH14040 (2014-2016, PI: Ondrej Kuda)<\/li>\n<\/ul>\n<h2>Our publications:<\/h2>\n<p>\u25ba Ondrej Kuda<sup>\u2709<\/sup> <strong>On the Complexity of PAHSA Research<\/strong>. Cell Metabolism 2018, Sep 20; DOI https:\/\/doi.org\/10.1016\/j.cmet.2018.09.006<\/p>\n<p>Comments on the methodological and conceptual problems when working with FAHFAs.<\/p>\n<p>fulltext at <a id=\"link\" href=\"https:\/\/www.cell.com\/cell-metabolism\/pdf\/S1550-4131(18)30571-0.pdf\" target=\"_blank\" rel=\"noopener\">https:\/\/www.cell.com\/cell-metabolism\/pdf\/S1550-4131(18)30571-0.pdf<\/a><\/p>\n<p>free fulltext link <a id=\"link\" href=\"https:\/\/authors.elsevier.com\/a\/1Xq8i5WXUlA-Mk\" target=\"_blank\" rel=\"noopener\">https:\/\/authors.elsevier.com\/a\/1Xq8i5WXUlA-Mk<\/a><\/p>\n<p>&nbsp;<\/p>\n<hr \/>\n<p>&nbsp;<\/p>\n<p>\u25ba Ondrej Kuda<sup>\u2709<\/sup>, Marie Brezinova, Jan Silhavy, Vladimir Landa, Vaclav Zidek, Chandra Dodia, Franziska Kreuchwig, Marek Vrbacky, Laurence Balas, Thierry Durand, Norbert H\u00fcbner, Aron B. Fisher, Jan Kopecky and Michal Pravenec <strong>Nrf2-mediated Antioxidant Defense and Peroxiredoxin 6 are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid<\/strong>. Diabetes 2018 Mar; db171087.; DOI https:\/\/doi.org\/10.2337\/db17-1087<\/p>\n<\/div>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-27435 aligncenter\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/g7vwbfcz1z6w4uhh0cdc-2.jpg\" alt=\"-\" width=\"700\" height=\"223\" title=\"\" srcset=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/g7vwbfcz1z6w4uhh0cdc-2.jpg 700w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/g7vwbfcz1z6w4uhh0cdc-2-300x96.jpg 300w\" sizes=\"(max-width: 700px) 100vw, 700px\" \/><\/p>\n<p>Omega-3 polyunsaturated fatty acids (omega-3) of marine origin alleviate inflammation, while having favorable metabolic effects. Omega-3 reduce the risk of development of cardiovascular disorders that are linked to obesity and type 2 diabetes, and also improve lipid metabolism. A complex research of omega-3-related mechanisms of action in mouse models of obesity at the Institute of Physiology CAS, clinical research on obese patients with type 2 diabetes in the Institute for Clinical and Experimental Medicine, and a collaboration with the Institute of Organic Chemistry and Biochemistry CAS led to the identification of structures of novel signaling molecules of lipid origin &#8211; esters of fatty acids and hydroxyl-fatty acids (FAHFA) &#8211; derived from docosahexaenoic acid (DHA): 13-DHAHLA, 9-DHAHLA a 14-DHAHDHA. These molecules, which are synthesized by adipose cells and exert anti-inflammatory effects, were detected in the serum and adipose tissue of both obese mice and diabetic patients following dietary intervention with omega-3. These newly discovered molecules, which can be endogenously synthesized when eating an appropriate diet, are involved in the beneficial health effects of omega-3 and have the potential for their wide use in the prevention and treatment of severe diseases.<\/p>\n<p>Chronic low-grade inflammation contributes to the development of diabetes, as well as cardiovascular, gastrointestinal and certain brain disorders. Lipids of marine origin help to prevent inflammatory diseases.<\/p>\n<p><a href=\"http:\/\/diabetes.diabetesjournals.org\/content\/65\/9\/2580\" target=\"_blank\" rel=\"noopener\">http:\/\/diabetes.diabetesjournals.org\/content\/65\/9\/2580<\/a><\/p>\n<p><a href=\"http:\/\/diabetes.diabetesjournals.org\/content\/65\/11\/3516.2\" target=\"_blank\" rel=\"noopener\">http:\/\/diabetes.diabetesjournals.org\/content\/65\/11\/3516.2<\/a> erratum &#8211; an incorrect version of the Supplementary Data was erroneously posted online and has been replaced with the correct version.<\/p>\n<p><strong>Purification of 13-DHAHLA<\/strong>: Organic synthesis of docosahexaenoic acid-13-hydroxylinoleic acid (13-DHAHLA) was performed according to Steglich esterification from docosahexaenoic acid (DHA) and 13-hydroxylinoleic acid (13-HODE). The product was purified using silica-based Ag<sup>+<\/sup> flash chromatography (low pressure silver-ion chromatography, Discovery Ag-Ion SPE sorbent, Sigma-Aldrich) and a combination of acetonitrile and acetone [12]).<\/p>\n<hr \/>\n<p>&nbsp;<\/p>\n<p>Kuda O. <strong>Bioactive metabolites of docosahexaenoic acid<\/strong>. Biochimie. Jan 2017, DOI: 10.1016\/j.biochi.2017.01.002<\/p>\n<p><a id=\"link\" href=\"http:\/\/dx.doi.org\/10.1016\/j.biochi.2017.01.002\" target=\"_blank\" rel=\"noopener\">http:\/\/www.sciencedirect.com\/science\/article\/pii\/S0300908416302218<\/a><\/p>\n<\/div>\n<p>An integrative overview of how DHA is metabolized emphasizing the derivatives that have been identified as bioactive.<\/p>\n<div class=\"content full\">\n<table style=\"height: 986px;\" border=\"0\" width=\"1210\" cellspacing=\"1\" cellpadding=\"1\" align=\"left\">\n<tbody>\n<tr>\n<td width=\"718.2\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-27437\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-811x1024.jpg\" alt=\"-\" width=\"696\" height=\"878\" title=\"\" srcset=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-811x1024.jpg 811w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-237x300.jpg 237w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-768x970.jpg 768w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-1216x1536.jpg 1216w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-1621x2048.jpg 1621w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/dha-bioactive-metabolites-overview-1-scaled.jpg 2026w\" sizes=\"(max-width: 696px) 100vw, 696px\" \/><\/td>\n<td>Legend:<br \/>\n13-DHAHLA, 13-(docosahexaenoyloxy)-hydroxylinoleic acid<br \/>\n14-DHAHDHA, 14-(docosahexaenoyloxy)-hydroxydocosahexaenoic acid<br \/>\n9-DHAHLA, 9-(docosahexaenoyloxy)-hydroxylinoleic acid<br \/>\nAT-, aspirin-triggered-<br \/>\nCEP, 2-(\u03c9-carboxyethyl)pyrrole<br \/>\nCOX, cyclooxygenase<br \/>\nDHEA, docosahexaenoyl ethanolamine<br \/>\nDHG, docosahexaenoyl glycerol<br \/>\ndiHDHA, dihydroxydocosahexaenoic acid<br \/>\ndiHDHEA, dihydroxy-DHEA<br \/>\ndiHDPA, dihydroxydocosapentaenoic acid<br \/>\nDPA, docosapentaenoic acid<br \/>\nDPEP, dipeptidase<br \/>\neMar, 13,14-epoxy-maresin<br \/>\nGGT, \u03b3-glutamyl transferase<br \/>\nGSH, glutathione<br \/>\nGST, glutathione S-transferase<br \/>\nGSTM4, glutathione S-transferase<br \/>\nHEDPEA, hydroxy-epoxy-docosapentaenoyl ethanolamine<br \/>\nHOHA, 4-hydroxy-7-oxohept-5-enoic acid<br \/>\nHpDHA, hydroperoxydocosahexaenoic acid<br \/>\nHpDHEA, hydroperoxy-DHEA<br \/>\nLOX, lipoxygenase<br \/>\nMCTR, Maresin conjugates in tissue regeneration<br \/>\nNAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D<br \/>\nNAT, N-acyltransferase<br \/>\nP450, cytochrome P450<br \/>\nPCTR, Protectin conjugates in tissue regeneration<br \/>\nPD, protectin D<br \/>\nPE, phosphatidylethanolamine<br \/>\nPGDH, hydroxyprostaglandin dehydrogenase<br \/>\nRCTR, Resolvin conjugates in tissue regeneration<br \/>\nROS, reactive oxygen species<br \/>\nRvD, resolvin D<br \/>\nsEH, soluble epoxide hydrolase<br \/>\ntriHDHA, trihydroxydocosahexaenoic acid<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"size-large wp-image-27439 aligncenter\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/bba-milk-graphical-abstract-1-1024x394.jpg\" alt=\"-\" width=\"800\" height=\"308\" title=\"\" srcset=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/bba-milk-graphical-abstract-1-1024x394.jpg 1024w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/bba-milk-graphical-abstract-1-300x115.jpg 300w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/bba-milk-graphical-abstract-1-768x295.jpg 768w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/bba-milk-graphical-abstract-1.jpg 1535w\" sizes=\"(max-width: 800px) 100vw, 800px\" \/><\/p>\n<p><a id=\"link\" href=\"https:\/\/authors.elsevier.com\/a\/1W5Ar4xeyFgE0F\" target=\"_blank\" rel=\"noopener\">fulltext share link till 01\/08\/2018<\/a><\/p>\n<p>&nbsp;<\/p>\n<hr \/>\n<p>Ondrej Kuda<sup>\u2709<\/sup>, Marie Brezinova, Jan Silhavy, Vladimir Landa, Vaclav Zidek, Chandra Dodia, Franziska Kreuchwig, Marek Vrbacky, Laurence Balas, Thierry Durand, Norbert H\u00fcbner, Aron B. Fisher, Jan Kopecky and Michal Pravenec <strong>Nrf2-mediated Antioxidant Defense and Peroxiredoxin 6 are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid<\/strong>. Diabetes 2018 Mar; db171087.; DOI https:\/\/doi.org\/10.2337\/db17-1087<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-large wp-image-27441\" src=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsa-proposed-pathway-1-1024x343.jpg\" alt=\"-\" width=\"800\" height=\"268\" title=\"\" srcset=\"https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsa-proposed-pathway-1-1024x343.jpg 1024w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsa-proposed-pathway-1-300x100.jpg 300w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsa-proposed-pathway-1-768x257.jpg 768w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsa-proposed-pathway-1-1536x514.jpg 1536w, https:\/\/fgu.cas.cz\/wp-content\/uploads\/2024\/08\/pahsa-proposed-pathway-1-2048x686.jpg 2048w\" sizes=\"(max-width: 800px) 100vw, 800px\" \/><\/p>\n<p>Comprehensive lipidomic analysis of rat white adipose tissue samples identified ~160 FAHFA regioisomers and QTL analysis highlighted several positional candidate genes in PAHSA metabolism. The results indicate that the synthesis of PAHSAs via carbohydrate-responsive element-binding protein (ChREBP)-driven <em>de novo<\/em> lipogenesis is linked to the adaptive antioxidant system and the remodelling of phospholipid hydroperoxides.<\/p>\n<p><a id=\"link\" href=\"https:\/\/doi.org\/10.2337\/db17-10877\" target=\"_blank\" rel=\"noopener\">fulltext<\/a><\/p>\n<p>&nbsp;<\/p>\n<hr \/>\n<p>\u25ba Ondrej Kuda<sup>\u2709<\/sup> <strong>On the Complexity of PAHSA Research<\/strong>. Cell Metabolism 2018, Sep 20; DOI https:\/\/doi.org\/10.1016\/j.cmet.2018.09.006<\/p>\n<p>Comments on the methodological and conceptual problems when working with FAHFAs.<\/p>\n<p>fulltext at <a id=\"link\" href=\"https:\/\/www.cell.com\/cell-metabolism\/pdf\/S1550-4131(18)30571-0.pdf\" target=\"_blank\" rel=\"noopener\">https:\/\/www.cell.com\/cell-metabolism\/pdf\/S1550-4131(18)30571-0.pdf<\/a><\/p>\n<p>free fulltext link <a id=\"link\" href=\"https:\/\/authors.elsevier.com\/a\/1Xq8i5WXUlA-Mk\" target=\"_blank\" rel=\"noopener\">https:\/\/authors.elsevier.com\/a\/1Xq8i5WXUlA-Mk<\/a><\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>White adipose tissue (WAT) is a complex endocrine organ and its low-grade inflammation in obesity contributes to the development of metabolic disorders. In 2014, a class of WAT-born lipid mediators &#8211; fatty acid esters of hydroxy fatty acids (FAHFA) was discovered [1]. FAHFAs are endogenous lipids with anti-inflammatory and anti-diabetic properties, including the enhancement of [&hellip;]<\/p>\n","protected":false},"author":1,"template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"oddeleni":[149],"poskytovatel":[],"stav-projektu":[210],"class_list":["post-30132","vyzkumny-projekt","type-vyzkumny-projekt","status-publish","hentry","oddeleni-adipose-tissue-biology","stav-projektu-finished-projects"],"acf":[],"_links":{"self":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/vyzkumny-projekt\/30132","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/vyzkumny-projekt"}],"about":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/types\/vyzkumny-projekt"}],"author":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/users\/1"}],"version-history":[{"count":0,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/vyzkumny-projekt\/30132\/revisions"}],"wp:attachment":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/media?parent=30132"}],"wp:term":[{"taxonomy":"oddeleni","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/oddeleni?post=30132"},{"taxonomy":"poskytovatel","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/poskytovatel?post=30132"},{"taxonomy":"stav-projektu","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/stav-projektu?post=30132"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}