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Branched fatty acid esters of hydroxy fatty acids (FAHFA)


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 - fatty acid esters of hydroxy fatty acids (FAHFA) was discovered. 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, 2], but the biosynthetic enzymes involved are unknown [11]. 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, 2, 10].

Network representation of FAHFA families linked according to the hydroxy-backbone and colored according to the esterified fatty acid [13][14].

FAHFAome

 

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. 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  the structures, effects  on WAT inflammation,  WAT glucose tolerance and molecular  mechanisms of signaling  of these new lipokines. Our results present a significant advance in research of the mechanisms connecting inflammation, metabolism, and nutritional lipids.

Our publications:

 

► Kristyna Brejchova, Laurence Balas, Veronika Paluchova, Marie Brezinova, Thierry Durand, Ondrej Kuda
Understanding FAHFAs: From Structure to Metabolic Regulation
Progress in Lipid Research, Volume 79, July 2020, 101053. DOI https://doi.org/10.1016/j.plipres.2020.101053 free fulltext PDF link

The discovery of branched fatty acid esters of hydroxy fatty acids (FAHFAs) in humans draw attention of many researches to their biological effects. Although FAHFAs were originally discovered in insects and plants, their introduction into the mammalian realm opened new horizons in bioactive lipid research. Hundreds of isomers from different families have been identified so far and their role in (patho) physiological processes is currently being explored. The family of palmitic acid esters of hydroxy stearic acids (PAHSAs), especially 5-PAHSA and 9-PAHSA regioisomers, stands out in the crowd of other FAHFAs for their anti-inflammatory and anti-diabetic effects. Beneficial effects of PAHSAs have been linked to metabolic disorders such as type 1 and type 2 diabetes, colitis, and chronic inflammation. Besides PAHSAs, a growing family of polyunsaturated FAHFAs exerts mainly immunomodulatory effects and biological roles of many other FAHFAs remains currently unknown. Therefore, FAHFAs represent unique lipid messengers capable of affecting many immunometabolic processes. The objective of this review is to summarize the knowledge concerning the diversity of FAHFAs, nomenclature, and their analysis and detection. Special attention is paid to the total syntheses of FAHFAs, optimal strategies, and to the formation of the stereocenter required for optically active molecules. Biosynthetic pathways of saturated and polyunsaturated FAHFAs in mammals and plants are reviewed together with their metabolism and degradation. Moreover, an overview of biological effects of branched FAHFAs is provided and many unanswered questions regarding FAHFAs are discussed.

  • Review of total syntheses of FAHFAs
  • FAHFA nomenclature & analytical procedures
  • Metabolism - synthesis and degradation
  • Biological effects on target organs
  • FAHFA-ome in human adipose tissue - network of 583 FAHFAs from 21 families


 

► Veronika Paluchova, Anders Vik, Tomas Cajka, Marie Brezinova, Kristyna Brejchova, Viktor Bugajev, Lubica Draberova, Petr Draber, Jana Buresova, Petra Kroupova, Kristina Bardova, Martin Rossmeisl, Jan Kopecky, Trond Vidar Hansen, Ondrej Kuda
Triacylglycerol-rich oils of marine origin are optimal nutrients for induction of polyunsaturated docosahexaenoic acid ester of hydroxy linoleic acid (13-DHAHLA) with anti-inflammatory properties in mice.
Molecular Nutrition and Food Research, 2020 Jun;64(11):e1901238 DOI https://doi.org/10.1002/mnfr.201901238

Scope Docosahexaenoic acid ester of hydroxy linoleic acid (DHAHLA) is a bioactive lipids with anti‐inflammatory properties from the family of fatty acid esters of hydroxy fatty acids (FAHFA). Methods and results To explore the biosynthesis of 13‐DHAHLA from dietary oils, C57BL/6N mice were gavaged for 8 days with various corn oil / marine oil mixtures containing the same amount of DHA. Plasma levels of omega‐3 FAHFAs were influenced by the lipid composition of the mixtures but did not reflect the changes in bioavailability of polyunsaturated fatty acids in plasma. Triacylglycerol‐bound DHA and linoleic acid served as more effective precursors for 13‐DHAHLA synthesis than DHA bound in phospholipids or wax esters. Both 13(S)‐ and 13(R)‐DHAHLA inhibited antigen and PGE2‐induced chemotaxis and degranulation of mast cells to a comparable extent and 13(S)‐DHAHLA was identified as the predominant isomer in mouse adipose tissue. Conclusion Here we identified the optimal nutritional source of DHA, which supports production of anti‐inflammatory FAHFAs, as triacylglycerol‐based marine oil and also revealed a possible role of triacylglycerols in the synthesis of FAHFA lipokines.

  • 13-DHAHLA is an anti-inflammatory lipid mediator.
  • The authors investigate DHA-rich marine oils as potential nutritional sources of 13-DHAHLA precursors and explore anti-inflammatory properties of the bioactive lipid.
  • The results suggest that triacylglycerol-based marine oils are superior to marine phospholipids and wax esters in the ability to increase levels of 13-DHAHLA in circulation.
  • Both 13(S)- and 13(R)-DHAHLA inhibited antigen and PGE2-induced chemotaxis and degranulation of mast cells.

 


 

► Melha Benlebna, Laurence Balas, Béatrice Bonafos, Laurence Pessemesse, Gilles Fouret, Claire Vigor, Sylvie Gaillet, Jacques Grober, Florence Bernex, Jean François Landrier, Ondrej Kuda, Thierry Durand, Charles Coudray, François Casas, Christine Feillet-Coudray
Long-term intake of 9-PAHPA or 9-OAHPA modulates favorably the basal metabolism and exerts an insulin sensitizing effect in obesogenic diet-fed mice.
European Journal of Nutrition, 2020 in press DOI https://doi.org/10.1007/s00394-020-02391-1

Purpose Fatty acid esters of hydroxy fatty acids (FAHFAs) are a large family of endogenous bioactive lipids. To date, most of the studied FAHFAs are branched regioisomers of Palmitic Acid Hydroxyl Stearic Acid (PAHSA) that were reported to possess anti-diabetic and anti-inflammatory activity in humans and rodents. Recently, we have demonstrated that 9-PAHPA or 9-OAHPA intake increased basal metabolism and enhanced insulin sensitivity in healthy control diet-fed mice but induced liver damage in some mice. The present work aims to explore whether a long-term intake of 9-PAHPA or 9-OAHPA may have similar effects in obesogenic diet-fed mice. Methods C57Bl6 mice were fed with a control or high fat-high sugar (HFHS) diets for 12 weeks. The HFHS diet was supplemented or not with 9-PAHPA or 9-OAHPA. Whole-body metabolism was explored. Glucose and lipid metabolism as well as mitochondrial activity and oxidative stress status were analyzed. Results As expected, the intake of HFHS diet led to obesity and lower insulin sensitivity with minor effects on liver parameters. The long-term intake of 9-PAHPA or 9-OAHPA modulated favorably the basal metabolism and improved insulin sensitivity as measured by insulin tolerance test. On the contrary to what we have reported previously in healthy mice, no marked effect for these FAHFAs was observed on liver metabolism of obese diabetic mice. Conclusion This study indicates that both 9-PAHPA and 9-OAHPA may have interesting insulin-sensitizing effects in obese mice with lower insulin sensitivity.

  • 9-PAHPA and 9-OAHPA increased insulin sensitivity in C57Bl/6J obese mice.
  • 9-PAHPA and 9-OAHPA did not affect liver metabolism.

 


 

► Melha Benlebna, Laurence Balas, Beatrice Bonafos, Laurence Pessemesse, Claire Vigor, Jacques Grober, Florence Bernex, Gilles Fouret, Veronika Paluchova, Sylvie Gaillet, Jean Francois Landrier, Ondrej Kuda, Thierry Durand, Charles Coudray, François Casas, Christine Feillet-Coudray
Long-term high dietary intake of 9-PAHPA or 9-OAHPA increases basal metabolism and insulin sensitivity but disrupts liver homeostasis in healthy mice.
Journal of Nutritional Biochemistry, Volume 79, May 2020, 108361, DOI https://doi.org/10.1016/j.jnutbio.2020.108361

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a new family of endogenous lipids recently discovered. Several studies reported that some FAHFAs have anti-diabetic and anti-inflammatory effects. The objective of this study was to explore the impact of two FAHFAs, 9-PAHPA or 9-OAHPA on the metabolism of mice. C57Bl/6 J male mice, 6-weeks old, were divided into 3 groups of 10 mice each. One group received a control diet and the two others groups received the control diet supplemented with 9-PAHPA or 9-OAHPA for 12 weeks. Mouse weight and body composition were monitored throughout the study. Some days before euthanasia, energy expenditure, glucose tolerance and insulin sensitivity were also determined. After sacrifice, blood and organs were collected for relevant molecular, biochemical and histological analyses. Although high intake of 9-PAHPA or 9-OAHPA increased basal metabolism, it had no direct effect on body weight. Interestingly, the 9-PAHPA or 9-OAHPA intake increased insulin sensitivity, but without modifying glucose tolerance. Nevertheless, 9-PAHPA intake induced a loss of glucose-stimulated insulin secretion. Surprisingly, both studied FAHFAs induced hepatic steatosis and fibrosis in some mice, which were more marked with 9-PAHPA. Finally, a slight remodeling of white adipose tissue was also observed with 9-PAHPA intake. In conclusion, the long-term high intake of 9-PAHPA or 9-OAHPA increased basal metabolism and insulin sensitivity in healthy mice. However, this effect, highly likely beneficial in a diabetic state, was accompanied by manifest liver damage in certain mice that should deserve special attention in both healthy and pathological studies.

  • 9-PAHPA and 9-OAHPA are two branched fatty acid esters of hydroxy fatty acids (FAHFAs)
  • These both FAHFAs increased basal metabolism in C57Bl/6J healthy mice
  • 9-PAHPA and 9-OAHPA increased insulin sensitivity in C57Bl/6J healthy mice
  • 9-PAHPA and 9-OAHPA induced hepatic steatosis and fibrosis in some C57Bl/6J mice

 


 

► Veronika Paluchova, Marina Oseeva, Marie Brezinova, Tomas Cajka, Kristina Bardova, Katerina Adamcova, Petr Zacek, Kristyna Brejchova, Laurence Balas, Hana Chodounska, Eva Kudova, Renate Schreiber, Rudolf Zechner, Thierry Durand, Martin Rossmeisl, Nada A. Abumrad, Jan Kopecky, Ondrej Kuda
Lipokine 5-PAHSA is Regulated by Adipose Triglyceride Lipase and Primes Adipocytes for de novo Lipogenesis in Mice.
Diabetes. 2020 Mar;69(3):300-312. DOI https://doi.org/10.2337/db19-0494

Branched esters of palmitic acid and hydroxy-stearic acid (PAHSA) are anti-inflammatory and anti-diabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the crosstalk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol/fatty acid (TAG/FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG-estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primed adipocytes for glucose metabolism in a different way from insulin, promoting DNL, and impeding TAG synthesis. In summary, our data revealed new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA, its relation to insulin action in adipocytes, and independently confirmed a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

 


 

► Marie Brezinova, Tomas Cajka, Marina Oseeva, Marek Stepan, Klara Dadova, Lenka Rossmeislova, Milos Matous, Michaela Siklova, Martin Rossmeisl, Ondrej Kuda
Exercise training induces insulin-sensitizing PAHSAs in adipose tissue of elderly women.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1865 (2020) 158576; online 16 November 2019, 158576; DOI https://doi.org/10.1016/j.bbalip.2019.158576

Adverse effects of aging can be delayed with life-style interventions. We examined how exercise training (ET) alone or combined with omega-3 polyunsaturated fatty acid (PUFA) affects serum and adipose tissue (AT) lipidome in older women. Fifty-five sedentary older women were included in the physical activity program and given either sunflower (Placebo) or wax esters-rich (Calanus) oil capsules for 4 months. Serum and subcutaneous abdominal AT samples were acquired while maximum rates of oxygen consumption (VO2 max), insulin sensitivity (hyperinsulinemic-euglycemic clamps) and comprehensive lipidome profiles were determined before and after the study. ET increased VO2 max in both groups. Lipidomics profiling revealed unusual serum triacylglycerols and phospholipids with ether-bound alkyls in the Calanus group, while ET generally induced shorter-chain triacylglycerols in AT, suggesting increased de novo lipogenesis. The latter was positively associated with whole-body insulin sensitivity. Unexpectedly, insulin-sensitizing lipokines from the family of branched palmitic acid esters of hydroxy stearic acid (PAHSAs) were elevated in both serum and AT after ET, while PAHSAs-containing triacylglycerols were detected in AT. ET stimulated beneficial changes in AT, including PAHSAs synthesis. Although the added value of omega-3 PUFA supplementation was not proven, our discovery can help understand the nature of the metabolic benefits of exercise.

  • Exercise training stimulates beneficial changes in adipose tissue of elderly women.
  • Exercise stimulates production of insulin-sensitizing lipid mediators PAHSAs.
  • Insulin sensitivity is associated with short chain TAGs in adipose tissue.
  • Ether lipids and TAG estolides were detected in serum and adipose tissue samples.

 


 

► Anders Vik, Trond Vidar Hansen, Ondrej Kuda
Synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic acid (13-DHAHLA).
Tetrahedron Letters Volume 60, Issue 52, 26 December 2019, 151331; DOI https://doi.org/10.1016/j.tetlet.2019.151331

Recently, several different classes of endogenous lipids have been reported that display antidiabetic and anti-inflammatory effects. Due to their minute presence in human samples, access to synthetic material of each enantiomer becomes necessary for exact structural elucidation and extensive biological evaluation. Herein we report the multi-milligram synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic acid (13-DHAHLA) from commercially available starting materials.

  • Syntheses of both enantiomers of 13-DHAHLA was achieved.
  • A recent and convenient protocol for making vinylic iodides was used.
  • Z-selective alkyne reduction was achieved by the use of activated zinc (Cu/Ag).
  • The Corey-Fuchs and the Ohira-Bestmann reactions were used to generate alkynes.

 


 

► Ondrej Kuda
On the Complexity of PAHSA Research.
Cell Metabolism Volume 28, ISSUE 4, P541-542, October 02, 2018; DOI https://doi.org/10.1016/j.cmet.2018.09.006

Comments on the methodological and conceptual problems when working with FAHFAs.

fulltext at https://www.cell.com/cell-metabolism/pdf/S1550-4131(18)30571-0.pdf

 


 

► Ondrej Kuda, Marie Brezinova, Jan Silhavy, Vladimir Landa, Vaclav Zidek, Chandra Dodia, Franziska Kreuchwig, Marek Vrbacky, Laurence Balas, Thierry Durand, Norbert Hübner, Aron B. Fisher, Jan Kopecky and Michal Pravenec
Nrf2-mediated Antioxidant Defense and Peroxiredoxin 6 are Linked to Biosynthesis of Palmitic Acid Ester of 9-Hydroxystearic Acid.
Diabetes 2018 Jun; 67(6): 1190-1199; DOI https://doi.org/10.2337/db17-1087

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 (Nrf2)-mediated antioxidant defense system (Prdx6, Mgst1, Mgst3), lipid-handling proteins (Cd36, Scd6, Acnat1, Acnat2, Baat), and the family of flavin containing monooxygenases (Fmo) as the positional candidate genes. Transgenic expression of Nrf2 and deletion of Prdx6 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.

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 de novo lipogenesis is linked to the adaptive antioxidant system and the remodelling of phospholipid hydroperoxides.

 


 

► Marie Brezinova, Ondrej Kuda, Jana Hansikova, Martina Rombaldova, Laurence Balas, Kristina Bardova, Thierry Durand, Martin Rossmeisl, Marcela Cerna, Zbynek Stranak, Jan Kopecky.
Levels of palmitic acid ester of hydroxystearic acid (PAHSA) are reduced in the breast milk of obese mothers.
BBA - Molecular and Cell Biology of Lipids 1863 (2018) 126–131; DOI https://doi.org/10.1016/j.bbalip.2017.11.004

To achieve optimal development of a newborn, breastfeeding is extensively recommended, but little is known about the role of non-nutritive bioactive milk components. We aimed to characterize the fatty acid esters of hydroxy fatty acids (FAHFAs), namely palmitic acid hydroxystearic acids (PAHSAs)—endogenous lipids with anti-inflammatory and anti-diabetic properties, in human breast milk. Breast milk samples from 30 lean (BMI = 19–23) and 23 obese (BMI > 30) women were collected 72 h postpartum. Adipose tissue and milk samples were harvested from C57BL/6J mice. FAHFA lipid profiles were measured using reverse phase and chiral liquid chromatography-mass spectrometry method. PAHSA regioisomers as well as other FAHFAs were present in both human and murine milk. Unexpectedly, the levels of 5-PAHSA were higher relative to other regioisomers. The separation of both regioisomers and enantiomers of PAHSAs revealed that both R- and S-enantiomers were present in the biological samples, and that the majority of the 5-PAHSA signal is of R configuration. Total PAHSA levels were positively associated with weight gain during pregnancy, and 5-PAHSA as well as total PAHSA levels were significantly lower in the milk of the obese compared to the lean mothers. Our results document for the first time the presence of lipid mediators from the FAHFA family in breast milk, while giving an insight into the stereochemistry of PAHSAs. They also indicate the negative effect of obesity on 5-PAHSA levels. Future studies will be needed to explore the role and mechanism of action of FAHFAs in breast milk.

  • FAHFAs are present in human and murine breast milk.
  • Levels of 5-PAHSA are negatively affected by obesity.
  • Stereochemistry of PAHSA regioisomers is explored
  • The majority of the 5-PAHSA signal is of R configuration


 

► Ondrej Kuda, Marie Brezinova, Martina Rombaldova, Barbora Slavikova, Martin Posta, Petr Beier, Petra Janovska, Jiri Veleba, Jan Kopecky, Jr., Eva Kudova, Terezie Pelikanova and Jan Kopecky
Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties.
Diabetes 2016 Sep; 65 (9): 2580-2590. https://doi.org/10.2337/db16-0385

White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans.

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.

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.

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.

Purification of 13-DHAHLA: 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+ flash chromatography (low pressure silver-ion chromatography, Discovery Ag-Ion SPE sorbent, Sigma-Aldrich) and a combination of acetonitrile and acetone [12]).


 

► Ondrej Kuda
Bioactive metabolites of docosahexaenoic acid.
Biochimie. Jan 2017, DOI: 10.1016/j.biochi.2017.01.002

Docosahexaenoic acid (DHA) is an essential fatty acid that is recognized as a beneficial dietary constituent and as a source of the anti-inflammatory specialized proresolving mediators (SPM): resolvins, protectins and maresins. Apart from SPMs, other metabolites of DHA also exert potent biological effects. This article summarizes current knowledge on the metabolic pathways involved in generation of DHA metabolites. Over 70 biologically active metabolites have been described, but are often discussed separately within specific research areas. This review follows DHA metabolism and attempts to integrate the diverse DHA metabolites emphasizing those with identified biological effects. DHA metabolites could be divided into DHA-derived SPMs, DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids. These bioactive metabolites have pleiotropic effects that include augmenting energy expenditure, stimulating lipid catabolism, modulating the immune response, helping to resolve inflammation, and promoting wound healing and tissue regeneration. As a result they have been shown to exert many beneficial actions: neuroprotection, anti-hypertension, anti-hyperalgesia, anti-arrhythmia, anti-tumorigenesis etc. Given the chemical structure of DHA, the number and geometry of double bonds, and the panel of enzymes metabolizing DHA, it is also likely that novel bioactive derivatives will be identified in the future.

  • Docosahexaenoic acid can be converted into a diverse set of bioactive metabolites.
  • Both oxygenated metabolites and DHA conjugates exert pleiotropic effects.
  • Structural elucidation and confirmation of their bioactions are crucial.
  • It is likely that novel DHA bioactive derivatives will be identified in the future.

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 DHA metabolites scheme

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Legend:
 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
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
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
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

 

Grants

Supported by:

  • Czech Science Foundation project no. 20-00317S (2020-2022, PI: Ondrej Kuda)
  • MEYS project no. LTAUSA18104 (2019-2022, PI: Ondrej Kuda)
  • Czech Academy of Sciences, Lumina Quaeruntur 2018 praemium
  • Czech Science Foundation project no. 17-10088Y (2017-2019, PI: Ondrej Kuda)
  • MEYS project no. LTAUSA17173 (2017-2019, PI: Ondrej Kuda)
  • MEYS project no. LH14040 (2014-2016, PI: Ondrej Kuda)

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