Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists?
BACKGROUND
Peroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARdelta) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARalpha agonists which lower lipid level, and glitazones as PPARgamma agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARalpha/gamma would be a logical approach. But synthetically developed PPARalpha/gamma dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases.


OBJECTIVE
Docosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present hypothesis suggests that the derivatives of these fatty acids are stronger PPAR agonists than the parent compounds. X-ray structures of PPARs indicate that alpha or beta derivatives of fatty acids would fit into PPARalpha/gamma binding cavity. Therefore, the derivatives will exhibit stronger affinities and activities than the parent compounds.


METHODS
Ligand binding assays and gene transactivation assays should be performed to test the hypothesis. Fluorescence-based methods are advantageous in binding assays, because they were found more suitable for fatty acid binding assays. In transactivation assays, care should be taken to remove contaminants from recombinant proteins.


CONCLUSIONS
Present hypothesis is framed on the basis of molecular structure of natural PPAR agonists. Small structural changes in the molecular structure of fatty acids have a great influence on activating different PPARs. Therefore, this hypothesis bridges the concept of natural PPAR agonists and the use of structural information in designing new drugs against diabetes and metabolic syndrome. The derivatives may also be used as anti-inflammatory and anticancer agents.
Gani
Osman A B S M
OA
Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway. Osman.Gani@fagmed.uit.no
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid