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 . Serine hydrolase carboxyl ester lipase  and threonine hydrolases  were identified as FAHFA-metabolizing enzymes. In humans, FAHFAs were detected in the serum, breast milk, meconium, and adipose tissues [1, 2, 10].
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.
► 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
► 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
► 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
► 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
► 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
► 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
► 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
► 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.
► 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
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
► 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
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/65/11/3516.2 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 ).
► Ondrej Kuda✉
Bioactive metabolites of docosahexaenoic acid.
Biochimie. Jan 2017, DOI: 10.1016/j.biochi.2017.01.002
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
DHEA, docosahexaenoyl ethanolamine
DHG, docosahexaenoyl glycerol
diHDHA, dihydroxydocosahexaenoic acid
diHDPA, dihydroxydocosapentaenoic acid
DPA, docosapentaenoic acid
GGT, γ-glutamyl transferase
GST, glutathione S-transferase
GSTM4, glutathione S-transferase
HEDPEA, hydroxy-epoxy-docosapentaenoyl ethanolamine
HOHA, 4-hydroxy-7-oxohept-5-enoic acid
HpDHA, hydroperoxydocosahexaenoic acid
MCTR, Maresin conjugates in tissue regeneration
NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D
P450, cytochrome P450
PCTR, Protectin conjugates in tissue regeneration
PD, protectin D
PGDH, hydroxyprostaglandin dehydrogenase
RCTR, Resolvin conjugates in tissue regeneration
ROS, reactive oxygen species
RvD, resolvin D
sEH, soluble epoxide hydrolase
triHDHA, trihydroxydocosahexaenoic acid
|IUPAC name||(9Z,11E)-13-[(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy]octadeca-9,11-dienoic acid|
|IUPAC name||(10E,12Z)-9-[(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy]octadeca-10,12-dienoic acid|
|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|
|IUPAC name||9-[(1-oxohexadecyl)oxy]-octadecanoic acid|