Docosahexaenoic Acid-Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties.
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.
Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Ondrej
0000-0001-7034-4536
O
Kuda
Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Marie
M
Brezinova
Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Martina
M
Rombaldova
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
Barbora
B
Slavikova
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
Martin
M
Posta
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
Petr
P
Beier
Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Petra
P
Janovska
Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Jiri
J
Veleba
Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic kopecky@biomed.cas.cz.
Jan
J
Kopecky
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
Eva
E
Kudova
Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Terezie
T
Pelikanova
Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic kopecky@biomed.cas.cz.
Jan
J
Kopecky
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000737:chemistry*; D004952:Esters / Q000737:chemistry* / Q000627:therapeutic use*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D019787:Linoleic Acid / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D004952:Esters; D005231:Fatty Acids, Unsaturated; D008070:Lipopolysaccharides; D004281:Docosahexaenoic Acids; C059528:14-hydroxydocosahexaenoic acid; D019787:Linoleic Acid