Anti-inflammatory effects of novel lipokines of fatty acid esters of hydroxy fatty acids family in obesity
White adipose tissue (WAT) is a complex endocrine organ and its low-grade inflammation in obesity contributes to the development of metabolic disorders. Omega-3 polyunsaturated fatty acids (PUFA) play an important role in resolution of inflammation and exert beneficial metabolic effects. In 2014, a class of WAT-born lipid mediators - fatty acid esters of hydroxy fatty acids ( FAHFA) derived from palmitic and stearic acid with anti-inflammatory and anti-diabetic properties was discovered [link]. Our hypothesis is that novel FAHFAs derived from omega-3 PUFA, with anti-inflammatory properties, could be found in mice and humans and that they can beneficially affect adipose tissue metabolism in obesity, especially low-grade inflammation. Using experiments in cell cultures, mice and humans we will explore the structures, effects on WAT inflammation, WAT glucose tolerance and molecular mechanisms of signaling of these new lipokines. Our results will presents a significant advance in research of the mechanisms connecting inflammation, metabolism, and nutritional lipids.
Related publications:
Kuda O, Brezinova M, Rombaldova M, Slavikova B, Posta M, Beier P, Janovska P, Veleba J, Kopecky J Jr, Kudova E, Pelikanova T, Kopecky J. Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties.
http://diabetes.diabetesjournals.org/content/65/9/2580
http://diabetes.diabetesjournals.org/content/65/11/3516.2 erratum - an incorrect version of the Supplementary Data was erroneously posted online and has been replaced with the correct version.
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.
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 - esters of fatty acids and hydroxyl-fatty acids (FAHFA) - 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.
Kuda O. Bioactive metabolites of docosahexaenoic acid. Biochimie. Jan 2017, DOI: 10.1016/j.biochi.2017.01.002
http://www.sciencedirect.com/science/article/pii/S0300908416302218
An integrative overview of how DHA is metabolized emphasizing the derivatives that have been identified as bioactive. Printable scheme as JPEG 
13-DHAHLA, 13-(docosahexaenoyloxy)-hydroxylinoleic acid 14-DHAHDHA, 14-(docosahexaenoyloxy)-hydroxydocosahexaenoic acid 9-DHAHLA, 9-(docosahexaenoyloxy)-hydroxylinoleic acid AT-, aspirin-triggered- CEP, 2-(ω-carboxyethyl)pyrrole COX, cyclooxygenase DHEA, docosahexaenoyl ethanolamine DHG, docosahexaenoyl glycerol diHDHA, dihydroxydocosahexaenoic acid diHDHEA, dihydroxy-DHEA diHDPA, dihydroxydocosapentaenoic acid DPA, docosapentaenoic acid DPEP, dipeptidase eMar, 13,14-epoxy-maresin GGT, γ-glutamyl transferase GSH, glutathione GST, glutathione S-transferase GSTM4, glutathione S-transferase HEDPEA, hydroxy-epoxy-docosapentaenoyl ethanolamine HOHA, 4-hydroxy-7-oxohept-5-enoic acid HpDHA, hydroperoxydocosahexaenoic acid HpDHEA, hydroperoxy-DHEA LOX, lipoxygenase MCTR, Maresin conjugates in tissue regeneration NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D NAT, N-acyltransferase P450, cytochrome P450 PCTR, Protectin conjugates in tissue regeneration PD, protectin D PE, phosphatidylethanolamine PGDH, hydroxyprostaglandin dehydrogenase RCTR, Resolvin conjugates in tissue regeneration ROS, reactive oxygen species RvD, resolvin D sEH, soluble epoxide hydrolase triHDHA, trihydroxydocosahexaenoic acid |
FAHFA structures:
| Common name | 13-DHAHLA |
| IUPAC name | (9Z,11E)-13-[(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy]octadeca-9,11-dienoic acid |
| SMILES | O=C(CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC)OC(CCCCC)\C=C\C=C/CCCCCCCC(=O)O |
| Molecular Formula | C40H62O4 |
| Molecular Weight | 606.91788 |
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|
| Common name | 9-DHAHLA |
| IUPAC name | (10E,12Z)-9-[(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy]octadeca-10,12-dienoic acid |
| SMILES | CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(=O)OC(CCCCCCCC(=O)O)\C=C\C=C/CCCCC |
| Molecular Formula | C40H62O4 |
| Molecular Weight | 606.91788 |
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|
| Common name | 14-DHAHDHA |
| IUPAC name | (4Z,7Z,10Z,12E,16Z,19Z)-14-[(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy]docosa-4,7,10,12,16,19-hexaenoic acid |
| SMILES | O=C(O)CC\C=C/C\C=C/C\C=C/C=C/C(C/C=C\C/C=C\CC)OC(=O)CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC |
| Molecular Formula | C44H62O4 |
| Molecular Weight | 654.96068 |
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| Common name | 9-PAHSA |
| IUPAC name | 9-[(1-oxohexadecyl)oxy]-octadecanoic acid |
| SMILES | OC(CCCCCCCC(OC(CCCCCCCCCCCCCCC)=O)CCCCCCCCC)=O |
| Molecular Formula | C34H66O4 |
| Molecular Weight | 538.88544 |
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Supported by the CSF project no. 17-10088Y (2017-2019, PI: Ondrej Kuda PhD., IPHYS) and MEYS project no. LH14040 (2014-2016, PI: Ondrej Kuda)
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