Hydroxy monounsaturated fatty acids as agonists for peroxisome proliferator-activated receptors.
The physiological and pathological role of oxidized polyunsaturated fatty acids (PUFAs) has been extensively studied, whereas those of hydroxy monounsaturated fatty acids (MUFAs) are not well understood. This study demonstrated that 11-hydroxy-(9Z)-octadecenoic acid ((9Z)-11-HOE), which was isolated from adlay seeds (Coix lacryma-jobi L. var. ma-yuen STAF.), can activate peroxisome proliferator-activated receptor (PPAR)alpha, delta and gamma in luciferase reporter assays more efficiently than (9Z)-octadecenoic acid (oleic acid), and to the same degree as linoleic acid. (9Z)-11-HOE increased the mRNA levels of UCP2 and CD36 in C2C12 myotubes and THP- 1 cells, respectively, and these effects were blocked by the PPARdelta- and gamma-specific antagonists GSK0660 and T0070907, respectively. Evaluation of the structure.activity relationship between hydroxy MUFAs and PPAR activation revealed that (9E)-11-HOE, the geometrical isomer of (9Z)-11-HOE, activated PPARs more potently than (9Z)-11-HOE, and that PPAR activation by hydroxyl MUFAs was not markedly influenced by the position of the hydroxy group or the double bond, although PPARdelta seemed to possess ligand specificity different to that of PPARalpha or gamma . Additionally, the finding that 11-hydroxy octadecanoic acid, the hydrogenated product of (9E)-11- HOE, was also capable of activating PPARs to a similar extent as (9E)-11-HOE indicates that the double bond in hydroxy MUFAs is not essential for PPAR activation. In conclusion, (9Z)-11-HOE derived from alday seeds and hydroxy MUFAs with a chain length of 16 or 18 acted as PPAR agonists. Hydroxylation of MUFAs may change these compounds from silent PPAR ligands to active PPAR agonists.
Yokoi
Hiroshi
H
Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
Mizukami
Hajime
H
Nagatsu
Akito
A
Tanabe
Hiroki
H
Inoue
Makoto
M
D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D031742:Coix / Q000737:chemistry*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D022781:Hepatocytes; D006801:Humans; D006865:Hydrogenation; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007536:Isomerism; D008024:Ligands; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D010938:Plant Oils / Q000302:isolation & purification / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012639:Seeds / Q000737:chemistry; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects*; D000071246:Uncoupling Protein 2
D018955:CD36 Antigens; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D007473:Ion Channels; D008024:Ligands; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D010938:Plant Oils; D012333:RNA, Messenger; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2